Microbial Ecosystems and “Malignant Until Proven Otherwise” Tumors

Introduction: Certain solid tumors exhibit suspicious ultrasound features – internal blood flow, feeder vessels, and echogenic reflectors – that earn them the label “malignant until proven otherwise.” These include malignancies across organs (breast, thyroid, liver, gallbladder, kidney, adrenal/nerve tissue, prostate, bladder, testis, uterus). Increasing evidence suggests that microbial ecosystems (gut dysbiosis, tumor-resident microbes, chronic infections, parasites, and commensals) can shape the tumor microenvironment and even the imaging phenotype of these cancers. Microbes may trigger chronic inflammation, alter hormonal and metabolic pathways, promote angiogenesis, or directly inhabit tumor tissue, thereby influencing tumor development and persistence. In this report, we review how microbial factors are implicated in each of these ultrasound-visible malignancies and highlight shared mechanisms across organ systems. We also note limitations in current literature and emerging research directions.

Shared Mechanisms: Microbes and the Tumor Microenvironment

Microorganisms can be integral components of the tumor ecosystem, affecting cancer hallmarks in multiple organs. Intratumoral bacteria are now recognized in many solid tumors, even those once thought sterile. Different cancer types harbor distinct microbial communities; for example, breast tumors contain a particularly rich and diverse bacterial populationpmc.ncbi.nlm.nih.gov. These bacteria often reside intracellularly within cancer cells and immune cellspmc.ncbi.nlm.nih.gov. Commensal microbes in tumor tissue can modulate tumorigenesis, progression, and therapy responses by altering local immune responses and inflammationpmc.ncbi.nlm.nih.gov. Notably, bacteria in the tumor microenvironment (TME) exert bidirectional effects: certain species drive cancer progression via pro-inflammatory cytokine secretion, activation of oncogenic signaling (e.g. NF-κB), and even inducing genomic instability, whereas other microbes have antitumor activity and can enhance responses to therapypmc.ncbi.nlm.nih.gov. Indeed, dysbiosis of the gut microbiome is now considered a hallmark of cancer, with well-documented examples like Fusobacterium nucleatumfueling colorectal cancer and Helicobacter species promoting GI cancerspmc.ncbi.nlm.nih.gov. Similar microbial influences are being reported in lung, breast, and prostate cancerspmc.ncbi.nlm.nih.gov.

Chronic inflammation is a unifying mechanism by which microbes promote tumorigenesis. Pathogenic bacteria or an imbalanced microbiome (“dysbiosis”) can create long-standing inflammatory states that encourage DNA damage, cell proliferation, and immune evasion. In general, dysbiosis promotes inflammation and tumor growth, whereas a healthy microbiome may exert protective, tumor-suppressive effectsasm.org. Many tumor-promoting infections (from periodontal pathogens to gut bacteria) activate inflammatory pathways like NF-κB and STAT3 in host tissues, leading to the release of interleukins (IL-6, IL-8, IL-1β), tumor necrosis factor (TNF), and other mediators that support malignant transformation. For example, Escherichia coli strains producing colibactin can directly induce DNA breaks and genomic instability in colon epithelial cellsfrontiersin.org. Helicobacter pylori in the stomach or Salmonella typhi in the intestine can activate β-catenin and Wnt pathways, driving uncontrolled cell growthfrontiersin.org. Microbial metabolites also play a role: lipopolysaccharide (LPS) from Gram-negative bacteria engages Toll-like receptor 4 (TLR4) on host cells, which in the liver drives a cascade of inflammation and fibrogenesis. In hepatocellular carcinoma, for instance, gut-derived LPS/TLR4 signaling promotes malignant progression by triggering hepatic progenitor cells to produce IL-6/TNF-α and by activating MyD88/STAT3, which upregulates VEGF and other pro-angiogenic and pro-proliferative factorsnature.com. Thus, bacteria can create a cytokine-rich, immune-suppressive niche that both fuels tumor growth and insulates the tumor from immune attack.

Angiogenesis and vascularity of tumors – critical for their growth and evident on Doppler ultrasound as internal blood flow or feeder vessels – can also be microbially driven. Chronic infections and inflammation are known to induce angiogenic factors. For example, Helicobacter infection in biliary cells increases NF-κB and nearly triples VEGF productionpmc.ncbi.nlm.nih.gov. Bacterial products like LPS, as noted, activate pathways (TLR4–MyD88–STAT3) that upregulate VEGF in tumorsnature.com. Certain bacteria such as Fusobacterium nucleatum have been shown to enhance endothelial cell proliferation and angiogenesis in colorectal tumors by upregulating VEGF and related signalslink.springer.com. Pathogens like Bartonella secrete factors (e.g. BafA autotransporter) that directly stimulate endothelial VEGF receptors, causing pathologic blood vessel growthpmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. Consistent with these findings, multiple studies report that tumors arising amidst infection are often hypervascular. In fact, bacterial colonization has been observed within tumor vasculature in cancers such as neuroendocrine tumors, colorectal and gastric cancers, cholangiocarcinoma, and otherspmc.ncbi.nlm.nih.gov. This microbial presence may further destabilize vessel integrity (through toxins that disrupt endothelial junctions) and promote vasculogenic mimicry – the formation of vessel-like channels by tumor cells – as part of the angiogenesis spectrumpmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. The result is highly perfused tumor tissue, correlating with the feeder vessels seen on imaging.

Echogenic reflectors on ultrasound often correspond to calcifications (e.g. microcalcifications or psammoma bodies) within tumors. These calcifications can arise from necrotic cell debris or metabolic deposits and are frequently associated with long-standing inflammation or cell turnover. Psammoma bodies, for instance, are lamellated calcifications classically found in papillary thyroid carcinoma, ovarian serous carcinoma, and some meningiomas. They are thought to form when fragile tumor papillae outgrow their blood supply, leading to ischemia, coagulative necrosis, and layered calcium depositionosmosis.orgosmosis.org. Notably, psammoma bodies are often a sign of chronic inflammation and can appear in benign inflammatory conditions as wellosmosis.org. This suggests that a chronically inflamed microenvironment – potentially driven by infection or dysbiosis – contributes to the microscopic calcifications that produce echogenic foci on ultrasound. In papillary thyroid carcinoma, for example, an association with Hashimoto’s thyroiditis (an autoimmune inflammatory state possibly linked to microbial triggers) is often noted, and abundant psammomatous calcifications tend to indicate more aggressive diseaseosmosis.orgosmosis.org. In sum, microbial influences that sustain inflammation and tissue damage over time may underlie some of the reflective calcific features we recognize as suspicious on imaging.

Across organ systems, common themes emerge: microbes (or the metabolites they produce) can maintain a pro-tumor microenvironment by continually activating inflammatory pathways, promoting angiogenesis (hence increased tumor vascularity on scans), and contributing to stromal changes like fibrosis or calcification. They may also modulate systemic factors such as hormones or the immune surveillance state in ways that favor tumor persistence. We now delve into each specific tumor type, highlighting known or proposed microbial contributions and how these might relate to the tumors’ development, maintenance, or imaging appearance.

Breast Cancer (Invasive Ductal and Lobular Carcinomas)

Breast carcinomas are among the most studied for microbiome–cancer interactions. In fact, breast tumor tissue harbors its own microbiota: a pan-cancer analysis found that breast cancers have a distinct and particularly diverse intratumoral microbiome, richer than that of several other tumor typespmc.ncbi.nlm.nih.gov. Bacterial DNA, RNA, and cell wall components have been detected inside breast cancer cells and associated immune cells, indicating active tumor-resident microbespmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. These bacteria might enter via circulation or ducts and then persist intracellularly, potentially altering local immune responses. For example, one study showed that depleting intratumoral bacteria in a mouse model of breast cancer reduced lung metastasis, hinting that the microbiota can influence metastatic behaviorcell.com. Some bacteria found in breast tumors (such as Methylobacterium or Sphingomonas in certain studies) are theorized to modulate estrogen signaling or immune cell recruitment, though specific mechanisms remain under investigation.

In addition to tumor-resident microbes, the gut and reproductive tract microbiomes have emerged as important remote regulators of breast cancer risk and phenotype. The gut microbiome, through its collection of estrogen-metabolizing genes (the estrobolome), helps regulate systemic estrogen levelsasm.orgasm.org. A healthy gut microbiota efficiently deconjugates and facilitates excretion of estrogens; however, dysbiosis can lead to excess estrogen reactivation and circulationasm.orgasm.org. Elevated lifetime estrogen exposure is a well-known driver of hormone receptor–positive breast cancers. Thus, gut dysbiosis may raise breast cancer risk by creating a hormonal milieu that stimulates mammary epithelial proliferation. Indeed, studies have found that postmenopausal women with breast cancer often have reduced gut microbial diversity and a lower abundance of estrogen-metabolizing bacteria, correlating with higher estrogen levelsasm.orgasm.org. Concurrently, the mammary gland and the breast ductal tissue have their own microbiome, including commensals like Lactobacillus and Streptococcus. These organisms might influence local inflammation or genomic stability in breast tissue. For instance, certain microbes can produce reactive oxygen species or other metabolites that damage DNA or alter gene expression in adjacent epithelial cells. Chronic low-grade inflammation in breast tissue – potentially stemming from microbial antigens – could promote an environment of repeated cell turnover and mutagenesis.

Microbial influences might also help explain some imaging features and progression patterns of breast tumors. Breast cancers that arise in an inflammation-rich environment (e.g. obesity-related dysbiosis or mastitis) may show more rapid angiogenesis and hence greater Doppler flow on ultrasound. Inflammatory breast cancer, an aggressive subtype, is characterized by extreme edema and dermal lymphatic invasion; some have hypothesized a microbial component (though none proven) given its erysipelatous presentation. Moreover, microcalcifications (echogenic reflectors on imaging) are commonly seen in ductal carcinoma in situ (DCIS) and invasive cancers. These calcifications often result from necrotic debris in ducts or lobules. A pro-inflammatory microbiome might accelerate such necrosis by both increasing cancer cell turnover and recruiting macrophages that release calcium deposits. While no specific bacterium is confirmed to cause breast tumor calcifications, it is noteworthy that chronic inflammation is linked to calcific deposits in many tissuesosmosis.org. Thus, a dysbiotic gut or breast microbiome that fuels chronic inflammation could indirectly contribute to the development of the microcalcifications we use to detect malignancy.

Limitations: The breast tumor microbiome field is still young. Most evidence is correlational – e.g. finding differences in bacterial communities between patients with and without breast cancer – rather than proving causation. It’s unclear if certain bacteria actively initiate breast carcinogenesis or simply colonize tumor tissue after it forms. Also, breast tumor microbiota vary between individuals, and technical issues (contamination or low biomass) are challenges. Nonetheless, the consistent finding of intracellular bacteria in breast cancer cells is strikingpmc.ncbi.nlm.nih.gov, and emerging data suggest these microbes can affect chemotherapy response and immune cell infiltration in tumorspmc.ncbi.nlm.nih.gov. Ongoing research aims to determine if modulating the gut or breast microbiome (through diet, probiotics, or antibiotics) could alter breast cancer outcomes.

Thyroid Carcinomas (Papillary, Follicular, Medullary)

Thyroid cancers – especially papillary thyroid carcinoma (PTC), the most common subtype – often present on ultrasound with microcalcifications (psammoma bodies) and internal vascularity. While thyroid tumors have not traditionally been linked to infections, recent studies suggest gut microbiome dysbiosis may influence thyroid cancer development and thyroid immune homeostasis. A 2019 study comparing gut bacteria in thyroid cancer patients versus healthy controls found significant differences in composition: patients with thyroid tumors had a higher relative abundance of certain Gram-negative genera like Neisseria and Streptococcus, and a lower abundance of beneficial butyrate-producing bacteria (Butyricimonas) and Lactobacilluspubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. This suggests a pro-inflammatory dysbiosis pattern. Butyrate-producing microbes are generally anti-inflammatory, so their depletion could permit more systemic or local inflammation, potentially affecting the thyroid gland environment.

One hypothesis is that gut dysbiosis might contribute to autoimmune thyroiditis (Hashimoto’s thyroiditis), an inflammatory condition that is a risk factor for PTC. Dysbiosis could alter gut permeability and immune regulation, leading to loss of tolerance to thyroid antigens. In turn, chronic thyroid inflammation could promote microenvironment changes conducive to carcinoma (e.g. oxidative stress, growth factors from immune cells). It’s known that psammoma bodies in PTC are often found alongside lymphocytic thyroiditis, and they are considered a sign of longstanding tissue damage and repairosmosis.orgosmosis.org. If certain bacteria systemically heighten inflammatory tone, they might accelerate the formation of these calcifications and drive the “malignant” ultrasound appearance of thyroid nodules with microcalcifications. Indeed, psammoma bodies can be detected by ultrasound in suspicious thyroid nodulesosmosis.org, and their presence correlates with PTC malignancyjournals.lww.com. Thus, microbial promotion of chronic inflammation is a plausible indirect contributor to that imaging feature.

Additionally, the gut-thyroid axis involves microbial effects on thyroid hormone metabolism. Gut bacteria can deconjugate thyroid hormones and alter enterohepatic cycling of T3/T4frontiersin.org. Dysbiosis might influence levels of TSH or thyroid hormones, which can impact thyroid cell proliferation. Some research has noted that gut microbiota profiles correlate with TSH levels and thyroid function indices in patientspubmed.ncbi.nlm.nih.gov, hinting that microbes could subtly affect the hormonal milieu that thyroid cells experience. Since elevated TSH is a growth stimulus for thyroid follicular cells, a dysbiotic microbiome that fails to produce metabolites like short-chain fatty acids (which can modulate TSH via neuroendocrine pathways) might lead to higher TSH and nodule growth. Moreover, chronic infections outside the gut have been explored: for example, Helicobacter pylori infection has been reported more frequently in patients with thyroid nodules and PTC than in controlsbrieflands.comjournals.plos.org, although not all studies agree. H. pylori might induce autoimmunity or molecular mimicry affecting the thyroid. Another organism, Yersinia enterocolitica, has long been suspected in autoimmune thyroid disease due to cross-reactivity with the TSH receptor, potentially linking a bacterial infection to goiter development.

For medullary thyroid carcinoma (MTC), which arises from calcitonin-producing C-cells, no clear microbial associations are known. MTC is often driven by RET proto-oncogene mutations (sometimes inherited in MEN syndromes) and does not obviously involve inflammation. It is likely that microbial factors play a minimal role in MTC compared to the more common differentiated thyroid cancers.

Limitations: The literature connecting microbiomes to thyroid cancer is relatively sparse and mostly consists of association studies. We know thyroid cancers happen frequently in iodine-deficient or radiation-exposed populations, but any microbial contribution is still speculative. The gut microbiome differences observed in thyroid cancer patientspubmed.ncbi.nlm.nih.gov do not prove causality – thyroid tumors themselves or altered diet could cause microbiome shifts. Also, small sample sizes and confounders (like thyroid medications or autoimmune status) complicate interpretations. So far, we lack direct evidence that treating dysbiosis (e.g. with probiotics) will alter thyroid nodule behavior. Nonetheless, the concept of a “microbiome–thyroid axis” has opened new questions, and further research may clarify whether manipulating gut bacteria could influence thyroid cancer risk or progression.

Hepatocellular Carcinoma (Liver Cancer)

Hepatocellular carcinoma (HCC) often manifests on imaging as a hypervascular tumor with chaotic internal blood flow – a reflection of intense angiogenesis. A major emerging paradigm in HCC biology is the gut–liver axis, where gut microbiome dysbiosis drives chronic liver inflammation and fibrogenesis, setting the stage for HCC. The liver is uniquely exposed to gut microbial products via the portal circulation. In chronic liver diseases (viral hepatitis, alcohol-related liver disease, or NASH), increased intestinal permeability allows translocation of microbial components like LPS into the liver. These activate Kupffer cells (liver macrophages) and hepatic stellate cells through pattern recognition receptors (TLR4, etc.), leading to cycles of inflammation, cell death, and regenerative proliferation. Over years, this environment can spawn dysplastic nodules and carcinoma.

Research shows that HCC patients have a distinct gut microbiome profile compared to cirrhotic patients who have not developed HCC. Generally, HCC is associated with an overrepresentation of pro-inflammatory and potentially pathogenic bacteria (e.g. Enterobacteriaceae, Streptococcus, Escherichia) and a reduction in beneficial commensals like Faecalibacterium and other butyrate producersnature.comnature.com. One consistent finding is an increase in LPS-producing Gram-negative bacteria in HCC patients’ intestinesnature.comnature.com. The excess LPS in the portal blood potently activates TLR4 in the liver. TLR4 signaling is a central hub linking dysbiosis to HCC progression: LPS–TLR4 interactions drive cancer stemness, angiogenesis, and invasive growth by inducing pathways such as AKT/SOX2 and JNK that promote epithelial–mesenchymal transitionnature.comnature.com. In experimental models, knocking out TLR4 or altering the microbiome can slow liver tumor formationnature.com. Clinically, HCC patients with early disease show higher serum LPS levels and an antibody response to LPS, correlating with risk of tumor recurrencenature.comnature.com.

Microbial products in the liver microenvironment also directly stimulate tumor angiogenesis. As noted earlier, LPS/TLR4 signaling in the liver activates MyD88/STAT3 and upregulates vascular endothelial growth factor (VEGF)nature.com. In chronic hepatitis, Kupffer cells release angiogenic cytokines (VEGF, PDGF) in response to bacterial ligands, contributing to the neovascularization of cirrhotic nodules and HCC. This explains why HCC lesions are extremely vascular (sometimes with arterio-portal shunts visible on Doppler ultrasound). The feeder vessels and brisk flow on ultrasound correlate with the inflammation-induced angiogenic drive partly mediated by gut microbes. Additionally, gut dysbiosis can alter bile acid metabolism – Clostridium and Ruminococcus species that increase in HCC can produce deoxycholic acid and other metabolites that further damage hepatocytes and stimulate angiogenesis or vasculogenic mimicry in tumorspmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.

Apart from bacteria, certain chronic infections are well-known causes of HCC: namely hepatitis B and C viruses. While viral, these pathogens illustrate how microbes initiate malignancy by causing years of necroinflammation in the liver. Interestingly, co-infections or microbiome changes might modulate these viruses’ carcinogenic potential. For instance, HCV-infected patients with heavier gut dysbiosis (e.g. higher endotoxin levels) have more severe fibrosis and higher HCC risk, suggesting synergy between viral and bacterial drivers of cancer. There is also emerging interest in the liver’s ownmicrobiome. Some studies have detected bacterial DNA within HCC tissues, though distinguishing blood-borne microbial fragments from true intratumoral bacteria is challenging. One report identified Proteobacteria DNA enriched in HCC tissue; another found that antibiotic-treated mice had reduced HCC growth, implying live bacteria contribute to tumor progressionpmc.ncbi.nlm.nih.gov. If viable bacteria reside in HCC, they might locally suppress anti-tumor immunity or help tumors evade therapy (as seen in pancreatic cancer where intratumoral bacteria metabolize chemotherapy drugs).

Limitations: Most evidence for microbiome involvement in HCC comes from animal models or observational human studies. It remains difficult to prove that specific bacterial strains cause human liver cancer, given confounders like diet and concomitant liver injury. Also, the “leaky gut” phenomenon in cirrhosis means microbial products are present, but pinpointing which microbial community changes are pathologic (versus a consequence of cirrhosis) is complex. Nonetheless, enough preclinical data exist that clinical trials are testing microbiome-modulating strategies – e.g. using antibiotics, probiotics (like Bifidobacterium or butyrate producers), or TLR4 inhibitors – to see if HCC outcomes improvenature.comnature.com. Early-phase studies suggest that altering the microbiome can reduce liver inflammation and even enhance immunotherapy in HCC patientsfrontiersin.org. Thus, while the field is nascent, the gut microbiome is firmly on the radar as both a biomarker and a potential therapeutic target in liver cancer.

Gallbladder Carcinoma

Gallbladder carcinoma (GBC) is a relatively rare but aggressive cancer often discovered late. It is classically associated with gallstones and chronic cholecystitis. A striking epidemiologic link exists between chronic Salmonella infection and gallbladder cancer. Regions with endemic typhoid fever (caused by Salmonella enterica serovar Typhi) have higher rates of GBC, and long-term carriers of S. Typhi (who harbor the bacteria in their gallbladder) are at significantly elevated risk of developing gallbladder carcinomasciencedirect.comsciencedirect.com. S. Typhi is now considered an oncogenic bacterium for gallbladder cancersciencedirect.com. The mechanism involves S. Typhi establishing resilient biofilms on gallstones and the gallbladder epithelium, leading to continuous mucosal irritation and delivery of bacterial toxins. Research has shown that bile-tolerant Salmonella form robust biofilms on cholesterol gallstone surfaces, protecting them from immune clearancepmc.ncbi.nlm.nih.govfrontiersin.org. Within these biofilms, Salmonella can persist for years, periodically secreting virulence factors. S. Typhi releases a cytolethal distending toxin and other effector molecules that can damage DNA or alter host cell signaling. Over time, this can facilitate the transformation of normal gallbladder epithelial cells into dysplastic and malignant cellssciencedirect.com. In chronic carriers, the gallbladder wall often exhibits dysplasia adjacent to Salmonella-laden gallstones, supporting this causal chain.

Chronic Salmonella infection also skews the immune microenvironment in the gallbladder. The persistent biofilm prompts ongoing infiltration of neutrophils, macrophages, and lymphocytes (chronic cholecystitis). These immune cells attempt to attack the bacteria but also produce genotoxic substances (nitric oxide, reactive oxygen species) that can injure epithelial DNA. They secrete growth factors like IL-6 and TNF that sustain epithelial proliferation – a classic recipe for cancer development in any chronically inflamed tissue. Salmonella LPS engaging TLR4 on gallbladder cells further drives NF-κB activation and inducible nitric oxide synthase (iNOS) expression, compounding the DNA damage and replicative stress on the epitheliumsciencedirect.com. Overexpression of cyclooxygenase-2 (COX-2) has been observed in chronic typhoid carriers’ gallbladders, linking bacterial inflammation to pro-tumorigenic prostaglandin signaling. In essence, the bacterium “alters the human immune system and establishes gallbladder cancer” as one review title aptly statessciencedirect.com.

These microbial effects can translate to notable imaging features. Chronic infection of the gallbladder often causes a calcification of the gallbladder wall known as “porcelain gallbladder,” which appears as echogenic curvature on ultrasound. Porcelain gallbladder itself is a risk factor for cancer, thought to result from dystrophic calcification after long-term inflammation. Moreover, GBCs associated with infection tend to be highly vascular and aggressive. On Doppler ultrasound, a gallbladder mass with internal blood flow and a feeding vessel in the gallbladder wall is very suspicious for malignancy. The angiogenesis in such tumors may be exacerbated by the constant inflammation from bacteria – macrophages and bacteria-stimulated gallbladder cells produce VEGF and PDGF, promoting a rich blood supply to the area (which initially is to heal inflammation but later feeds the tumor). Echogenic foci may also be present in these tumors if gallstones or calcifications are intertwined with the mass. Indeed, some GBCs form on the scaffold of a stone that has a biofilm; ultrasound might show the mixed echogenicity of a stone-tumor complex.

It’s not only Salmonella: other microbes have been investigated in biliary cancers. Some studies have detected Helicobacter species DNA (including H. pylori and H. bilis) in gallbladder carcinoma tissues. Helicobacter bilis, for example, can infect bile ducts and in animal models promotes cholangiocarcinoma by activating NF-κB and inducing VEGFpmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. While the gallbladder is slightly different anatomy, it’s plausible that Helicobacter in bile contributes to gallbladder tumorigenesis similarly. Regions with high liver fluke (parasite) infection (e.g. Opisthorchis viverrini in Thailand) suffer cholangiocarcinoma rather than GBC; however, some cases of gallbladder cancer have been noted in fluke-infected patients, suggesting parasites creating a pro-cancer biliary milieu broadly.

Limitations: Gallbladder cancer’s link to S. Typhi is supported by epidemiological and molecular evidence, but direct intervention proof is difficult (deliberately eradicating Salmonella carriers to see if cancer rates drop would be ideal but logistically challenging). Also, not all gallbladder cancers are infection-related; many in the West are associated with stones but not Salmonella (e.g. mechanical irritation, high bile acids may play roles). The gallbladder microbiomebeyond known pathogens is not well characterized – a healthy gallbladder likely has few bacteria due to bile’s antimicrobial properties, but gallstone disease may allow colonization by E. coli, Klebsiella, etc. It remains to be studied whether these commensal bile-resistant bacteria contribute meaningfully to gallbladder carcinogenesis in the absence of overt typhoid infection. Nevertheless, the paradigm of a biofilm–inflammation–cancer sequence in the gallbladder is a compelling example of microbes driving a malignancy in an otherwise sterile organ. It underscores the importance of chronic infection control (e.g. treating carriers, promoting sanitation to reduce typhoid) as an aspect of cancer prevention in endemic areas.

Renal Cell Carcinoma (Kidney Cancer)

Renal cell carcinoma (RCC), particularly clear cell RCC, is typically identified on imaging as a solid renal mass with internal vascular signals and sometimes calcifications. Traditionally, RCC has not been linked to infectious causes (unlike squamous bladder cancer with Schistosoma, for example). However, recent research has begun exploring the microbiome’s role in kidney tumors from two angles: the influence of the gut microbiome on systemic factors relevant to RCC, and the presence of a resident microbiome within kidney tumor tissue.

Systemically, the gut microbiome might affect RCC risk and progression through immune modulation and metabolism. Obesity and hypertension are risk factors for RCC, and the gut microbiota influences both body fat and blood pressure via metabolites (like short-chain fatty acids). Dysbiosis could thus indirectly contribute to the pro-tumor environment (e.g. via insulin resistance or chronic low-grade inflammation accompanying obesity). More directly, gut microbes can shape the efficacy of the immune system’s surveillance for tumors. It’s been found that the gut microbiota composition correlates with how RCC patients respond to immunotherapy (checkpoint inhibitors)pmc.ncbi.nlm.nih.gov. For instance, antibiotics that disrupt gut flora were linked to poorer survival in metastatic RCC patients on immunotherapyfrontiersin.org. This suggests a healthy microbiome is needed for optimal anti-cancer immune activity. Certain bacterial profiles (rich in Akkermansia or Bifidobacterium) have been associated with better responses, implying these commensals might prime the immune system against the tumor. Conversely, pro-inflammatory dysbiosis might accelerate RCC progression by maintaining a systemic inflammatory milieu (elevated IL-6, CRP levels are often seen in advanced RCC).

Intriguingly, studies have identified bacterial DNA and even live bacteria within kidney tumors. The kidney was historically thought to be sterile, but DNA sequencing of renal tissue has overturned that notion. A 2019 study on a small patient set found dozens of bacterial species present in RCC tissues, with tumor samples having higher microbial content than adjacent normal kidneyfrontiersin.orgfrontiersin.org. Predominant phyla included Proteobacteria, Firmicutes, and Actinobacteria (common gut and environmental bacteria phyla). Some genera detected only in tumors included Spirosomaand Mycoplasma, whereas normal kidney had others like Staphylococcus and Streptococcus that were less represented in tumorsfrontiersin.org. A more recent study reported that Fusobacterium nucleatum (known from colorectal cancer) and Streptococcus agalactiae were among the most abundant species in tumor tissue compared to normal kidneyfrontiersin.org. The presence of F. nucleatum in RCC is striking, as it’s a known oncobacterium in the colon; its presence might indicate seeding via the bloodstream or an immunosuppressed niche allowing its growth. These intratumoral bacteria could affect the tumor by locally modulating immune cells. For example, F. nucleatum is known to drive myeloid-derived suppressor cell (MDSC) accumulation and T-cell dysfunction in colon tumors; if similar occurs in the kidney, the bacteria could help RCC evade immune attack.

Another potential role of intratumoral bacteria is influencing angiogenesis. While not yet confirmed in RCC, analogies from other cancers suggest bacteria could reside near endothelial cells and alter vessel formation. Bacteria in tumors can secrete proteases and factors that remodel the extracellular matrix, potentially facilitating the formation of irregular vascular channels. RCC is already a highly vascular tumor (often producing VEGF due to VHL gene loss), so the added presence of bacteria might exacerbate vascular leakage or inflammation around vessels. It’s worth noting that long-standing renal infections (like xanthogranulomatous pyelonephritis caused by Proteus or E. coli) can create a mass that mimics RCC on imaging, with calcifications and staghorn stones (which are biofilm-laden). Though xanthogranulomatous pyelonephritis is not a cancer, it demonstrates how chronic bacteria-driven inflammation in the kidney can form a tumor-like lesion. This raises the question: could subclinical, chronic colonization of the kidney contribute to true RCC formation over years? No direct causal microbe for RCC has been found, but the concept is being explored.

Limitations: The kidney tumor microbiome research is in its infancy. There is a risk of contamination in detecting bacteria from surgically removed kidney tissues, so findings must be interpreted cautiously. Moreover, unlike GI organs, the kidney doesn’t have a clear exposure route for microbes except via the bloodstream or ascending urinary tract infections. Most UTIs affect the bladder rather than the kidney cortex where RCC arises, so how bacteria would establish in a kidney tumor is still puzzling. We also note that known risk factors for RCC (smoking, obesity, von Hippel–Lindau mutations) have no obvious microbial link. Therefore, microbes might be co-factors or passengers rather than primary triggers in RCC. Nonetheless, the correlation between certain bacteria and tumor vs normal tissuefrontiersin.orgfrontiersin.org suggests something non-random is occurring. Future studies and culturing efforts will clarify if kidney tumors support unique bacterial ecosystems and whether manipulating these can benefit patients (for example, using probiotics to enhance immunotherapy, as one trial with CBM588 probiotic showed improved responses in RCCsciencedirect.com).

Neuroblastoma

Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system (often arising in the adrenal medulla) that is detectable on ultrasound in infants as an adrenal or abdominal mass with internal blood flow and sometimes calcifications. Being an embryonal tumor, one might not expect a large role for microbes in its initiation. Indeed, there is no known infectious cause of neuroblastoma, and the literature on microbiome interactions is very limited. However, researchers have started to consider indirect links, such as how the early-life gut microbiome might influence the developing immune system and thereby affect neuroblastoma progression or therapy responses.

Children with high-risk neuroblastoma often exhibit an immunosuppressive tumor microenvironment. The NB tumors can cause immune evasion by secreting factors that inhibit T cells and natural killer (NK) cells. Some initial studies have asked whether gut microbial composition correlates with these immune features. For example, one analysis found that pediatric neuroblastoma patients had alterations in their gut microbiome compared to healthy children, including differences in taxa that produce short-chain fatty acids and regulate inflammationpmc.ncbi.nlm.nih.gov. Notably, the differences did not seem to simply reflect maternal microbiome transfer (meaning they might develop postnatally). Though causation isn’t established, one hypothesis is that a gut microbiome lacking certain beneficial microbes could result in weaker systemic anti-tumor immunity. In mice, it’s known that germ-free conditions or antibiotic-treated conditions impair aspects of immune development (like Th1/Th17 balance), which could conceivably let a nascent tumor like NB grow unchecked.

Another angle is microbial metabolites affecting tumor biology. The gut microbiota produces molecules that cross into circulation and can influence distant tissues – for instance, butyrate, propionate, and other metabolites can modulate gene expression via epigenetic mechanisms. In neuroblastoma cell lines, differentiation and apoptosis pathways are important (some treatments use retinoic acid to force NB cells to mature). It’s speculative, but if gut dysbiosis leads to a shortage of metabolites that normally promote cellular differentiation or anti-oxidative capacity, NB cells might remain in a more primitive, aggressive state. There has been interest in whether certain microbial metabolites (like polysaccharide A from Bacteroides fragilis or others) could boost anti-tumor immune responses in NB by activating dendritic cells or T cells in the gut that then migrate to the tumor.

While intratumoral bacteria have been documented in some adult cancers, it’s essentially unstudied in neuroblastoma. Given NB often presents in infants as young as a few months, it seems unlikely that bacteria would have had time to colonize the tumor or that a long-term infection could drive its development (since gestational influences are more relevant). However, a case report exists of NB co-occurring with infection: one report described a testicular neuroblastoma (very rare) in an infant, accompanied by a Salmonella abscess in the tumorpmc.ncbi.nlm.nih.gov. In that case, the Salmonella likely infected an existing tumor, rather than caused it. It does illustrate that NB tissue can be immunocompromised enough to allow microbial growth (perhaps due to necrosis in the tumor). Pathologists sometimes notice dystrophic calcifications in neuroblastomas (which can make them visible on imaging); these calcifications could result from necrosis in the tumor core, potentially with granulomatous reaction. If infections occur in NB (even opportunistically), they might contribute to such calcific scarring.

Limitations: Overall, concrete evidence linking microbes to neuroblastoma initiation or progression is virtually absent – hence it has been dubbed a “virgin island” in onco-microbiome researchpmc.ncbi.nlm.nih.gov. Most of the discussion is theoretical or extrapolated from general principles of tumor immunology. The developing infant microbiome is complex and also influenced by cancer treatments (antibiotics given during therapy, etc.). One Mendelian randomization study hinted at a “causal relationship” between certain gut microbial taxa and NB riskjournals.asm.org, but the results need validation. As it stands, any contribution of microbial ecosystems to neuroblastoma’s biology is speculative. However, given the success in other cancers of modulating the microbiome to improve therapy, it’s conceivable that in the future, adjunct probiotics or microbiome-based interventions could be tested in NB patients (for example, to reduce treatment toxicity or improve immunotherapy, if applicable). The field remains open and in need of dedicated studies.

Prostate Adenocarcinoma

The prostate gland, although internal, is accessible to microbes via the urinary tract and ejaculatory ducts. There is longstanding interest in whether chronic prostatitis (inflammation of the prostate) predisposes to prostate adenocarcinoma. Chronic inflammation can lead to genomic damage in prostate epithelium, and proliferative inflammatory atrophy lesions in the prostate are considered potential precursors to cancer. Several studies have implicated a specific bacterium, Propionibacterium acnes (recently renamed Cutibacterium acnes), in chronic prostate inflammation. P. acnes is best known for causing acne on skin, but it has been found in the prostate tissue of a large fraction of men – in one study, cultured from ~60% of prostate cancer specimens versus 26% of benign prostate controlspmc.ncbi.nlm.nih.gov. This anaerobic gram-positive rod can reside in the prostate, likely introduced via the urethra or hematogenously, and it tends to induce a Th17-mediated inflammatory response.

In vitro, P. acnes infection triggers prostatic epithelial cells to secrete inflammatory cytokines like IL-6, IL-8, and GM-CSFpmc.ncbi.nlm.nih.gov. This cytokine release recruits immune cells and can create an environment rich in oxidative radicals and growth factors. One experiment demonstrated that a P. acnes isolate caused healthy prostate cells to develop chronic inflammation and even pathological changes resembling prostatitis when introduced in micejournals.plos.orgclinicsinoncology.com. Over time, such inflammation might lead to accumulation of DNA damage (via ROS and nitric oxide). IL-6 is also a driver of STAT3 activation, which in the prostate can promote survival of initiated cancer cells and progression to androgen independence.

Beyond P. acnes, other microbes have been investigated: studies have found traces of viruses (like xenotropic murine retrovirus or HPV) in some prostate cancers, though causality is not established. Urinary tract infections (UTIs) caused by E. coli or other coliforms might ascend to the prostate and cause acute prostatitis; repeated infections theoretically could contribute to a chronic inflammatory milieu. However, epidemiologic data linking common UTIs to prostate cancer are inconclusive. The prostate is also prone to sexually transmitted infection exposures (e.g. gonorrhea, Trichomonas). Some case-control studies suggested a history of certain STIs modestly increased prostate cancer risk, again hinting that inflammation from infection could be a promoting factor.

The prostate microbiome concept has emerged from DNA sequencing of prostatic fluid and tissues. It appears the healthy prostate harbors a variety of bacteria at low levels (perhaps via the urethra). In prostate cancer patients, sequencing has shown an overrepresentation of certain genera like Propionibacterium, Staphylococcus, and Escherichia/Shigella in tumor tissuefrontiersin.orgsciencedirect.com. While these may simply reflect presence in the urinary tract, some could actively influence tumor biology. For example, Propionibacterium not only incites inflammation but might also modulate local hormone metabolism. There is speculation that bacteria could produce enzymes affecting testosterone or dihydrotestosterone levels locally, potentially impacting tumor growth (since prostate cancer is androgen-driven). Moreover, tumors with high P. acnes load have been noted to have more abundant immunosuppressive T-regulatory cells in the microenvironmentmdpi.com, suggesting the infection could paradoxically help the tumor evade immune attack by skewing the immune response.

On imaging, prostate adenocarcinoma is usually evaluated by MRI more than ultrasound these days, but transrectal ultrasound (TRUS) can detect hypoechoic lesions. Doppler ultrasound may show increased vascularity in prostate tumors. Chronic inflammation due to infection would also lead to increased blood flow (as seen in prostatitis on Doppler). It is possible that some of the hypervascularity or hyperemia in and around a tumor nodule could be partly inflammatory. For instance, a cancer focus with P. acnes infection might recruit inflammatory cells and neovessels, making the area even more Doppler-positive. Calcifications (prostatic calculi) are common in chronic prostatitis; these appear as echogenic foci on ultrasound but are typically benign. However, it’s conceivable that a long-infected prostate could accumulate calcifications and also develop cancer in the same region, intertwining infection signs and malignancy on imaging. So far, no specific ultrasound feature is definitively tied to microbes, but a gland with heterogeneous echo texture and increased blood flow diffusely could indicate coexistent prostatitis alongside cancer.

Limitations: Prostate cancer is extremely common, and teasing out microbial contributions amid numerous risk factors (age, genetics, diet) is difficult. The evidence for P. acnes in prostate cancer is intriguing (with multiple studies isolating the organism from tumors), but it is not absolute proof of causation. It may be that P. acnes preferentially grows in cancerous prostate tissue (which is often immunologically altered) rather than causes it. Large prospective studies would be needed to see if men with P. acnes-driven chronic prostatitis have higher incidence of cancer. Another limitation is that the prostate is a compartment that’s challenging to sample without contamination; some bacteria identified might come from the rectal flora during biopsy. Nonetheless, the prostate–microbiome link is being actively researched. If chronic prostate infections indeed contribute to oncogenesis, it raises the possibility of using anti-inflammatory or antibiotic therapies as part of prostate cancer prevention or management. Already, there is interest in whether aspirin or COX-2 inhibitors (targeting inflammation) reduce prostate cancer mortality, which might parallel how H. pylori eradication reduces stomach cancer risk. In summary, while microbes are not a primary known cause of prostate adenocarcinoma, they likely serve as secondary enablers in some men by providing the inflammatory fuel that helps latent tumor cells emerge and thrive.

Urothelial Carcinoma (Bladder Cancer)

Bladder cancer, particularly urothelial carcinoma of the bladder, often appears on ultrasound as an irregular intravesical mass with blood flow. Bladder cancer’s strongest known risk factors are smoking and chemical exposures, but chronic infection and inflammation also play a role, especially for certain subtypes. The most dramatic example is Schistosoma haematobium infection (urogenital schistosomiasis). S. haematobium is a parasitic blood fluke whose eggs embed in the bladder wall, causing decades of granulomatous inflammation. This chronic irritation can lead to dysplasia and squamous cell carcinoma of the bladder. In regions of Africa and the Middle East where schistosomiasis is endemic, up to 75% of bladder cancers are infection-related (often squamous histology rather than urothelial)journals.asm.orglink.springer.com. Schistosome eggs on ultrasound can appear as echogenic foci, and calcified eggs cause a “calcified bladder wall” appearance. These calcifications (from dead eggs) plus the neovascularization from inflammation yield a thick, hyperemic bladder on imaging that is “malignant until proven otherwise.” Indeed, the International Agency for Research on Cancer (IARC) classifies S. haematobium as a Group 1 definitive carcinogen for bladder cancerlink.springer.com.

The mechanism by which S. haematobium induces cancer parallels bacteria-induced pathways: eggs trapped in the bladder wall incite chronic immune response, with macrophages and eosinophils releasing enzymes and reactive speciesthat damage neighboring urothelial DNA. The parasite also produces antigens that can act as mitogens. Chronic schistosomal cystitis involves constant tissue repair and proliferation, laying the groundwork for malignant transformation. There is evidence that S. haematobium infection leads to upregulation of β-catenin signaling and alterations in the p53 pathway in urothelial cells, which are common in tumor developmentpmc.ncbi.nlm.nih.govjournals.asm.org. Moreover, the microbiome may modulate schistosome effects: studies of urine microbiome during schistosomiasis found changes in bacterial communities that could further influence inflammationjournals.plos.org. For example, urogenital schistosomiasis was associated with shifts in Proteobacteria and Firmicutes in urine, and these bacteria could interact with the host immune response in synergy or antagonism with the parasite.

Even outside of schistosomiasis, bacterial UTIs and the urinary microbiome are factors under study in bladder cancer. It was long believed urine in the bladder is sterile, but modern sequencing has identified a resident urinary microbiome (especially in females). In bladder cancer patients, researchers have noted differences in urinary microbial composition: some studies found higher abundance of Acinetobacter, Anaerococcus, or Streptococcus species in bladder cancer urine compared to controlssciencedirect.comsciencedirect.com. It’s hypothesized that these bacteria might contribute to a chronic inflammatory state in the bladder mucosa. Certain UTI bacteria can produce nitrite from dietary nitrates; nitrites can form nitrosamines, which are known bladder carcinogens (similar to how bacteria in the stomach can form nitrosamines implicated in gastric cancer). Recurrent UTIs, as seen in patients with long-term catheters, often lead to squamous metaplasia and squamous bladder cancer, again highlighting that persistent inflammation or injurypredisposes to malignancy.

One interesting finding is that a healthy urinary microbiome (dominated by Lactobacillus in women, for instance) might be protective, whereas a dysbiotic one (with more gram-negatives or anaerobes) could be harmful. Additionally, the bladder tumor microenvironment might itself select for certain bacteria. A recent study found that non-muscle-invasive bladder cancers treated with intravesical BCG (an immunotherapy using live attenuated Mycobacterium bovis) had better responses in patients whose baseline urinary microbiome included specific organisms that possibly synergize with BCG’s immune activationsciencedirect.comsciencedirect.com. This underscores that microbes can influence therapy outcomes in bladder cancer too.

Imaging considerations: Chronic infection in the bladder, be it bacterial or parasitic, leads to a thickened, fibrotic, and hypervascular bladder wall – which can mimic or coexist with tumor. The feeder vessels seen entering a bladder tumor on ultrasound are typically due to tumor-driven angiogenesis; however, inflammatory angiogenesis from chronic cystitis can also increase vascular markings. Echogenic reflectors might be seen if there are calcified Schistosome eggs or bladder stones associated with infection. In ultrasound, differentiating a purely inflammatory mass (like a granuloma or phlegmon) from a neoplasm can be challenging without further tests. Often they coexist (as with Schistosoma where tumors arise in an inflamed bladder). Color Doppler showing focal increased flow often tilts toward neoplasm. It's worth noting that S. haematobium eggs have a characteristic appearance on pathology (oval with a terminal spine) and often calcify; their presence in a bladder tumor confirms the infection-cancer association.

Limitations: Outside of schistosomiasis, the evidence for common bacterial involvement in bladder carcinogenesis is still preliminary. Unlike stomach or colon cancer, no single bacterium (besides H. pylori in stomach) is known to strongly predispose to bladder cancer. Smoking-related bladder carcinogenesis likely dwarfs any microbial effect in many populations. Also, the bladder’s exposure to environmental carcinogens (excreted in urine) complicates attribution – e.g. aromatic amines from smoking accumulate in urine and cause DNA adducts in the urothelium. Infections might play more of a role as promoters or in specific subsets (e.g. chronic Foley catheter patients). Nevertheless, the microbiome-immunity link is a hot topic. A 2025 review emphasized that the microbiome (gut and urinary) has critical roles in modulating immune response to bladder cancer, and microbial metabolites can shape local and systemic cancer immunologysciencedirect.comsciencedirect.com. As immunotherapy becomes a mainstay for advanced bladder cancer, understanding and harnessing the microbiome (perhaps via fecal transplants or probiotics to improve response) is an active area of researchsciencedirect.com. In conclusion, while microbes are not the primary cause of most urothelial carcinomas, they can influence the disease’s development and progression, particularly in the context of chronic infection/inflammation scenarios.

Seminoma (Testicular Germ Cell Tumor)

Seminoma is a germ cell tumor of the testis, typically occurring in young adult males. On ultrasound, a seminoma classically appears as a homogeneous hypoechoic intratesticular mass with robust internal vascularity on Doppler – essentially always considered “malignant until proven otherwise” given that non-cancerous masses (like infarctions or granulomas) are rare in the testis. When it comes to microbial factors, seminomas have no established link to infections or microbiome influences. Testicular germ cell tumors are largely driven by genetic and developmental factors (such as dysgenesis of the testis, cryptorchidism, and KIT/RAS pathway mutations). There is no equivalent to an HPV or H. pylori in testicular cancer etiology.

That said, we can explore a few tangential observations. The testes are an immune-privileged site, meaning immune activity is tightly regulated there to protect sperm. This immune privilege might also allow tumor cells to grow with less interference from immune surveillance. Whether the microbiome of the body influences this immune environment is unstudied. It’s conceivable that systemic inflammation or infection (which can break immune tolerance or alter cytokine profiles) might indirectly impact a developing testicular tumor’s interplay with the immune system. For example, severe orchitis (testicular infection) from mumps virus in puberty has been mentioned historically as a possible risk factor for testis damage, but its link to germ cell tumor is not proven. No consistent association between viral infections (mumps, EBV, etc.) and seminoma has been found, aside from some exploratory studies detecting viral antibodies. One older study noted high seroprevalence of EBV in testicular cancer patients, proposing a “possible infectious origin” for a subsetauajournals.org, but this remains speculative and not widely accepted.

In terms of intratumoral microbiota, testicular cancers have not been examined in the same way as other solid tumors for bacterial content. It is possible that due to the blood-testis barrier and the rapid growth of germ cell tumors, there is limited opportunity for microbes to colonize them. Additionally, many seminomas present and are treated quickly (orchiectomy), so there’s little time for an indolent tumor-microbe equilibrium to establish (unlike, say, colon tumors that grow slowly alongside gut bacteria). One unusual case report documented a post-operative infection in a seminoma: after orchiectomy, an abscess grew in the residual testis tissue infected by Salmonella saintpaul, likely due to contamination or bacteremia in an immune-suppressed patientpmc.ncbi.nlm.nih.gov. This is a reminder that after tumor disruption, infection can occur, but it doesn’t imply microbes were present before.

Could maternal microbiome or infections during pregnancy influence seminoma development (since germ cell tumor initiation is thought to happen in utero)? This is a very nascent area of thought. Some have hypothesized that maternal exposure to pathogens or changes in vaginal microbiome might affect the fetus’s germ cells or hormonal milieu, potentially contributing to testicular germ cell tumor risk. However, no concrete evidence exists for this. The rise in testicular cancer incidence in many countries is more commonly attributed to environmental endocrine disruptors and delayed child-bearing, rather than infectious causes.

Limitations: In summary, seminoma stands out among the listed tumors as one with minimal connection to microbial ecosystems in current knowledge. We have to acknowledge that an absence of evidence is not evidence of absence – the testicular tumor microenvironment’s microbiome has simply not been deeply investigated. But given what is known about seminoma (its cells originate from primordial germ cells that failed to differentiate properly), it’s hard to fit microbes into that origin story. Seminomas also are highly curable and prompt an immune response (they often have many tumor-infiltrating lymphocytes). It would be interesting to know if the gut microbiome could affect the success of immune response or therapy in seminoma patients (for instance, via influencing toxicity or recovery during chemotherapy), but these are peripheral considerations. As of now, unlike many other cancers, we do not have identified “tumor-resident” bacteria or chronic infections that predispose to seminoma. The focus for preventing and managing seminoma remains on known risk factors (like undescended testis) and genetic factors, rather than any microbial intervention.

Endometrial Carcinoma

Endometrial carcinoma (cancer of the uterine lining) is commonly detected on ultrasound as an abnormally thickened endometrium with increased vascularity and sometimes irregular echogenic foci. The pathogenetic driver for the majority (Type I endometrioid carcinoma) is unopposed estrogen exposure, often related to obesity or hormone therapy. However, emerging research implicates both the gut microbiome and the local uterine microbiome in modulating risk and progression of endometrial cancer. It turns out the uterus is not sterile, as once assumed – low levels of bacteria can be found in the endometrium even in healthy women, and dysbiosis in this niche may contribute to chronic inflammation and altered estrogen metabolism in the endometriumpmc.ncbi.nlm.nih.gov.

One way the gut microbiome influences endometrial cancer is through the estrobolome, similar to breast cancer. Obese women (who have higher endometrial cancer risk) often have gut dysbiosis characterized by fewer beneficial microbes and more LPS-producing bacteria. This leads to systemic inflammation and also higher circulating estrogen (because dysbiosis reduces estrogen excretion)pmc.ncbi.nlm.nih.govaacrjournals.org. The excess estrogen continually stimulates the endometrial lining, causing hyperplasia and possibly malignant transformation. A recent review noted that estrobolome dysbiosis can raise estrogen levels, contributing to early endometrial carcinogenesisaacrjournals.orgipa-biotics.org. In addition, gut microbiota imbalances might influence insulin resistance and adipokines in obesity, further creating a pro-tumor environment for the endometrium (insulin and IGF can stimulate endometrial cell proliferation).

The endometrial (uterine) microbiome itself has garnered attention. Studies have found that women with endometrial cancer often have a different endometrial microbial profile compared to healthy controls or those with benign conditions. Notably, Lactobacillus, which dominates a healthy vagina and possibly upper tract, is often depleted in endometrial cancer patients, whereas anaerobes like Gardnerella, Prevotella, and Atopobium are increasedfrontiersin.orgnature.com. These latter bacteria are associated with bacterial vaginosis and chronic endometritis. Chronic subclinical endometritis (inflammation of the uterine lining) can result from such dysbiosis, leading to the release of pro-inflammatory cytokines (IL-1β, TNFα, etc.) locally. Over time, this may promote a microenvironment of oxidative stress and increased cell turnover in the endometrium. In fact, persistent inflammation and immune disruption due to endometrial dysbiosis is suspected to increase endometrial cancer riskpmc.ncbi.nlm.nih.govnature.com. For example, Porphyromonas and Anaerococcus species (common in periodontal and vaginal dysbiosis) have been identified more frequently in endometrial cancer tissue; they could be acting similarly to how Fusobacterium acts in colon cancer – by recruiting myeloid cells that suppress adaptive immunity and by directly promoting tumor cell invasiveness.

Another intriguing connection is between microbiome and therapy response in endometrial cancer. Preliminary data suggest that the gut microbiome might affect how patients respond to immunotherapy (checkpoint inhibitors) for endometrial cancer. Given that mismatch repair-deficient endometrial cancers (with microsatellite instability) are treated with immunotherapy and these tumors have high mutation load, the role of gut bacteria in priming immune response could be relevant (as it is in melanoma and other cancers). There’s also speculation that modulating the vaginal microbiome (e.g., restoring Lactobacillus dominance) could be a strategy for chemoprevention, since a Lactobacillus-rich environment is less inflammatory and could decrease HPV persistence in cervical cancer prevention – by analogy, perhaps reducing chronic endometritis in the uterus.

In terms of imaging phenotype, a highly vascular endometrial lesion on Doppler ultrasound is more likely malignant. Chronic inflammation from infection or dysbiosis in the uterus tends to increase vascularity as well (think of how endometritis can cause increased blood flow on ultrasound). Thus, an endometrium that has been subject to years of low-grade inflammation (due to microbial imbalance) might develop a richer vascular network, which a tumor can then exploit for growth – appearing as pronounced color Doppler signals. Echogenic reflectors within an endometrial tumor could represent necrosis or calcifications; interestingly, extensive psammomatous calcifications have been reported in some high-grade endometrial carcinomaspmc.ncbi.nlm.nih.govosmosis.org. Psammoma bodies in endometrial serous carcinoma are rare but when present, they indicate chronic processes at play (similar to ovarian serous tumors). It’s conceivable that chronic inflammation (possibly from an infectious cause) in the endometrium contributes to those calcific deposits.

Limitations: Research on the “microbiome-uterus axis” is relatively new. Much of it is associative – e.g., showing differences in microbial communities with cancer – without proving that dysbiosis causes cancer. The female genital tract microbiome is dynamic and influenced by age, hormones, sexual activity, and hygiene practices, which makes standardizing studies hard. Additionally, collecting uncontaminated endometrial samples is challenging (cervical/vaginal bacteria can mix in). Therefore, while correlations abound (e.g., Lactobacillus depletion in cancer), causation is not established. We also must consider that endometrial cancer itself (or associated necrosis and bleeding) might create an environment that selects for certain bacteria, rather than bacteria causing the cancer. Despite these caveats, the consistent theme of inflammation linking microbiome to endometrial carcinogenesis is compelling. Investigators are now looking at whether probiotics or antibiotics could alter endometrial hyperplasia outcomes, or whether the gut microbiome composition could serve as a non-invasive biomarker for early detection of endometrial cancercancernursingtoday.comnature.com. This is an evolving field, and future studies will better clarify the cause-effect relationship and potentially open new avenues for prevention (like targeting the gut-estrogen axis via microbial means).

Conclusion and Emerging Perspectives

Across the diverse malignancies reviewed – from breast and thyroid cancers to HCC, bladder cancer, and others – microbial ecosystems clearly emerge as influential players in the tumor microenvironment. In some cases, specific pathogens are established carcinogens (e.g. H. pylori for gastric cancer, S. Typhi for gallbladder cancer, Schistosoma for bladder SCC), underscoring that chronic infection can drive cancer initiation. In other tumors, the microbiome’s role is more subtle, acting more as a facilitator of tumor progression and modulator of immune response than a direct cause. Common mechanisms include:

• Chronic Inflammation: Virtually all evidence converges on inflammation as the bridge between microbes and cancer. Microbe-induced inflammation provides growth signals (like NF-κB driven cytokines) and DNA damage that support tumor development across organ systemspmc.ncbi.nlm.nih.govsciencedirect.com.

• Angiogenesis and Vascular Modulation: Microbial products such as LPS can upregulate angiogenic factors (VEGF, IL-8), leading to the hypervascular tumors seen on ultrasoundnature.com. Some bacteria even reside in tumor vessels, influencing their structurepmc.ncbi.nlm.nih.gov.

• Immune Evasion: Certain intratumoral bacteria polarize immune cells toward suppressive phenotypes (e.g. M2 macrophages, Tregs), helping tumors hide. Examples include gut bacteria affecting checkpoint immunotherapy efficacysciencedirect.comsciencedirect.com, and F. nucleatum in tumors blocking NK cell activity.

• Hormonal and Metabolic Effects: The gut microbiome’s regulation of estrogen (the estrobolome) links microbial dysbiosis to hormone-driven cancers like breast and endometriumasm.orgaacrjournals.org. Microbes also produce metabolites that can be pro-tumor (e.g. secondary bile acids in liver cancer) or anti-tumor (SCFAs).

• Direct Genotoxicity: Some bacteria produce toxins (colibactin, CDT, etc.) that directly break DNA or induce mutations in host cells, potentially initiating cancerous changesfrontiersin.org.

Importantly, many of these mechanisms are shared across multiple organs, illustrating how a dysregulated microbiome might create a “field effect” for malignancy. For instance, the concept of dysbiosis as a systemic cancer risk factor is gaining tractionpmc.ncbi.nlm.nih.gov. Mice with certain gut flora develop more liver, breast, or colon tumors, and transferring those microbes can transmit the risk, highlighting causal links. In our review, we noted that even in cancers without a single culprit microbe, patients often show microbiome alterations (e.g. thyroid and renal cancers have gut or tissue dysbiosis signatures). These commonalities hint that targeting microbial ecosystems could become a broad anti-cancer strategy. Indeed, probiotics and antibiotics are being tested in clinical trials as adjuncts to immunotherapy or chemotherapy in various cancerspmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.

Imaging phenotype connection: While still a developing area, our exploration suggests that some ultrasound hallmarks of malignancy have biological underpinnings tied to microbes. The presence of feeder vessels/internal flow relates to angiogenesis, which microbes can stimulate. Echogenic reflectors (calcifications) often indicate chronic processes or necrosis, which infections promote. Thus, the radiologic maxim “malignant until proven otherwise” could, in some cases, be reframed as “chronically inflamed until proven otherwise” – acknowledging that malignancy and long-term inflammation/infection are two sides of the same coin. For example, a hypervascular thyroid nodule with microcalcifications is likely PTC; it is interesting to speculate that an inflammatory microenvironment (perhaps influenced by gut or thyroid microbiota) contributed to those very features that we detect.

Limitations of current knowledge: Despite intriguing correlations, there are significant gaps. Many studies are cross-sectional, making it hard to tell cause from effect. Tumor-associated microbes might be passengers taking advantage of the tumor niche rather than drivers. There’s also publication bias and heterogeneity in methods (different sequencing targets, contamination controls) that sometimes yield conflicting results (e.g. one study finds a genus up in cancer, another finds it down). Particularly in less-studied cancers (neuroblastoma, seminoma), our discussion was necessarily extrapolative. We also note that most microbiome-cancer research to date has focused on the gut microbiome; local microbiomes (tumor-resident or organ-specific, like the breast or endometrium) are harder to characterize due to low biomass, but likely very important. Furthermore, the interactions between different microbes (bacteria, viruses, fungi, parasites) within the tumor ecosystem remain largely unexplored – tumors might have polymicrobial communities that jointly influence outcome.

Emerging clinical implications: A deeper understanding of microbial-tumor interactions could open novel preventative and therapeutic avenues. For instance, cancer prevention could include infection control (e.g. deworming programs to prevent Schistosoma-bladder cancer, H. pylori eradication to prevent gastric cancer, hepatitis virus vaccination, and perhaps S. Typhi vaccination to curb gallbladder cancer in endemic areassciencedirect.com). Screening of microbiome patterns might help identify individuals at risk (“microbial signatures” as early biomarkers for cancers like HCC or endometrial cancernature.comcancernursingtoday.com). Therapeutically, there is growing interest in microbiome modulation – using prebiotics, probiotics, or fecal microbiota transplantation – to enhance anticancer immunity. For example, adding a probiotic Clostridium butyricum in a mouse model suppressed angiogenesis and metastasis in the gut by restoring butyrate and downregulating pro-angiogenic signalspmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. In RCC patients, a probiotic bacterium CBM588 improved response to immunotherapysciencedirect.com. Additionally, bacteria-based tumor therapies are in development: attenuated Salmonella strains have been used to selectively colonize and destroy tumor tissue, essentially leveraging bacteria’s affinity for hypoxic tumor corespmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. These efforts echo historical observations like Coley’s toxins (using bacterial products to stimulate immune attack on cancer).

In conclusion, the interplay between microbial ecosystems and malignancies labeled “malignant until proven otherwise” by imaging is a frontier of research that bridges oncology, immunology, and microbiology. While each organ’s context differs, the recurring theme is that tumors are not isolated entities but part of a complex host–microbe ecosystem. The microbiome can be a tumor’s ally (fostering growth and immune escape) or its enemy (promoting anti-tumor immunity or direct tumoricidal effects), depending on the context. Unraveling these relationships offers exciting possibilities: we might one day incorporate microbiome analyses into cancer diagnostics and harness microbes or their metabolites as therapeutic tools. However, realizing these clinical gains will require overcoming current limitations with rigorous, longitudinal studies and clinical trials. As of now, our understanding is still evolving, but it reinforces a more holistic view of cancer biology – one that includes our microbial inhabitants as key participants in the drama of malignancy.

References:

1. Nejman, D. et al. (2020). “The human tumor microbiome is composed of tumor type–specific intracellular bacteria.” Science, 368(6494):973-980pmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.

2. Sepich-Poore, G. D. et al. (2021). “The microbiome and human cancer.” Science, 371(6536):eabc4552.

3. Xuan, C. et al. (2014). “Microbial dysbiosis is associated with human breast cancer.” PLoS ONE, 9(1):e83744.

4. Shirke, A. et al. (2025). “How the Gut Microbiome Influences Breast Cancer.” ASM, Oct 31, 2025asm.orgasm.org.

5. Zhang, J. et al. (2019). “Dysbiosis of the gut microbiome is associated with thyroid cancer and thyroid nodules.” Endocrine, 64(3):564-574pubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov.

6. Chen, Y. et al. (2022). “Roles of the gut microbiota in hepatocellular carcinoma: from the gut dysbiosis to the intratumoral microbiota.” Cell Death Discov., 8(1):481nature.comnature.com.

7. Upadhayay, A. et al. (2022). “Salmonella typhi induced oncogenesis in gallbladder cancer: Co-relation and progression.” Adv. Cancer Biol. - Metastasis, 4:100032sciencedirect.comsciencedirect.com.

8. Vianden, C. et al. (2023). “The microbiome of the prostate tumor microenvironment.” Eur. Urol., 83(5):466-475sciencedirect.commdpi.com.

9. Golshani, M. et al. (2025). “Understanding the microbiome as a mediator of bladder cancer progression and therapeutic response.” Urol. Oncol., 43(4):254-265sciencedirect.comsciencedirect.com.

10. Wang, Y. et al. (2022). “Gut and Endometrial Microbiome Dysbiosis: A New Emergent Risk Factor for Endometrial Cancer.” Cancers (Basel), 14(15):3809pmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.

11. Jun, X. et al. (2023). “Microbiome in Neuroblastoma: A Virgin Island in the World of Onco-Immunology.” Cancers, 15(5):1511.

12. Liu, Y. et al. (2023). “Intratumoral Microbiota: Impact on Cancer Progression and Immune Modulation.” Clin. Transl. Immunology, 12(4):e1420pmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.

13. Dong, M. et al. (2023). “The bidirectional regulatory effects of bacteria on blood vessels in the tumor microenvironment.” Front. Microbiol., 14:1248916pmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.

14. Fassi Fehri, L. et al. (2011). “Propionibacterium acnes induces IL-6 and IL-8 in prostate epithelial cells: implication of chronic inflammation in prostate adenocarcinoma.” Br. J. Cancer, 105(3):473-482pmc.ncbi.nlm.nih.gov.

15. Osorno, J. et al. (2021). “Female genital tract microbiome dysbiosis in endometrial cancer.” Gynecol. Oncol., 161(3):617-628frontiersin.orgpmc.ncbi.nlm.nih.gov.

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