The discovery of microorganisms, such as bacteria, fungi, and parasites, inside cancer cells dates back to 1884. However, when 19th-century research methods failed to identify these microorganisms, the theory of microbial involvement in cancer lost traction.(24,58) Since then, oncology (cancer) and microbiology (bacteria) have largely been treated as separate fields in research and medicine.
Recent scientific advancements have reignited interest in the role of microorganisms in cancer development. Researchers are now studying how these microorganisms may influence tumor cell behavior, with the goal of uncovering new insights that could guide future treatments and diagnostic approaches.
This article discusses the nature of intratumoral and intracellular bacteria, how bacteria enter tumors and cancer cells, their effects on cancer progression and treatment, and the ongoing research in this field.
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Intratumoral and/or Intracellular Bacteria
Bacteria may be found in the tumor microenvironment, which is often immune-suppressed, where they can access nutrients and avoid some immune responses.(53) The distinction between “intratumoral” and “intracellular” bacteria commonly refers to their location.
- Intracellular bacteria reside inside cancer cells, affecting cancer cells from within.
- Intratumoral bacteria are located in the tumor adjacent to the cancer cells and influence cancer cells from outside interactions within the tumor microenvironment.
Getting Inside the Cancer Cells
Bacteria are typically about 1/10 the size of the average cancer cell and invade cancer cells through two primary methods: the trigger or the zipper mechanisms.(2,49,57)
- Trigger: Bacteria “break into” the cancer cells by manipulating the cell’s surface, forcing the cancer cell to engulf the bacteria, similar to a burglar prying open a door.
- Zipper: Similar to a lock and key, proteins on the bacteria’s cell surface bind to receptors on the cancer cell’s surface. This interaction causes the cancer cell membrane to "zip" around the bacteria, drawing them inside methodically.
After the bacteria enter the cancer cell, they are typically enclosed in a vacuole —a membrane-bound compartment within the cell that helps manage waste and foreign substances. Some bacteria, such as Shigella, have evolved mechanisms to escape the vacuole and survive within the host cell, allowing them to avoid immune detection and replicate freely.(55) Other bacteria use different strategies to bypass and escape the vacuole.(63)
Once bacteria are inside cancer cells, they use the cancer cell’s machinery for their own survival and replication. While doing this, bacteria feed off of the cancer's nutrients and often escape immune surveillance (62). These bacteria are often called tumor-resident intracellular microbiota (TRIM).
The percentage of cancers containing bacterial DNA may vary by cancer type – ranging from 14% for melanoma to over 60% for breast, pancreatic, and bone cancers.(53) Cancers that have suggested bacterial presence include:
o Melanoma
o Breast
o Liver
o Oral
o Lung
o Gastric
o Cervical
o Prostate
Where Do the Bacteria Come From?
Most intratumoral and intracellular bacteria come from the body’s own microbiota, including healthy bacteria from the GI tract, mouth, nose, and throat. These bacteria may become harmful when they move to tissues where they don’t belong. As tumors grow, they can disrupt epithelial and mucosal barriers, allowing bacteria from adjacent tissues to invade.
This situation is especially relevant in colorectal cancer, where the proximity of the GI tract makes bacterial migration into the tumor microenvironment more likely.(59) Because of this, intratumoral and intracellular bacteria in colorectal cancer is one of the most studied areas. The exact mechanisms by which bacteria travel to tumor microenvironments is unclear, but bacteria are capable of traveling through the bloodstream and the lymphatic system where they can spread to other tissues.(56,61)
Since bacteria typically found in the GI tract has been observed in other cancer types (ex. breast and liver), researchers are actively investigating the connection between intratumoral microbiota and the gut microbiome.(18,26,34)
Some cases have also reported intratumoral or intracellular bacteria that originated from food, water, or surgical procedure contamination.(25,28,45)
The Chicken or The Egg
Which came first? Many wonder whether bacteria can cause cancer or whether they merely thrive in the cancerous environment. Currently, Helicobacter Pylori (H. Pylori), an intracellular bacteria, in gastric cancer is the first and only bacterium recognized by the World Health Organization (WHO) to potentially cause cancer (carcinogen).
H. Pylori can induce chronic inflammation and adversely affect cellular pathways, triggering gastritis and subsequently gastric cancer.(43) While this bacterium’s carcinogenic role is established, researchers are just beginning to uncover other bacteria’s role in cancer development and metastasis.
Intratumoral and Intracellular Bacteria Effects on Cancer
Intracellular bacteria, which invade and live inside cancer cells, can alter cell signaling pathways, cause chronic inflammation, and evade immune detection — all factors that contribute to cancer progression and metastasis.
- Bacterial invasion in cells can trigger strong immune responses, including the recruitment of immune cells through pro-inflammatory signaling cascades.
- Certain bacteria may produce toxins, such as reactive oxygen species (ROS), and metabolites that promote DNA damage, leading to mutations that drive cancer development.(20,33,54)
- Recent studies have highlighted the role of intracellular bacteria in promoting breast cancer metastasis.(37)
Growing evidence suggests that bacteria can interfere with the effectiveness of cancer treatments, such as chemotherapy and immunotherapy. For example:
- Some studies suggest bacteria could interact with chemotherapy drugs, potentially impacting their effectiveness, or influence immune responses in ways that might affect immunotherapy outcomes. This interference can cause drug resistance and increase the likelihood of cancer relapse after treatment.
- Additionally, bacteria can inhibit autophagy in cancer cells—a process by which cells degrade and recycle their components—further contributing to chemotherapy resistance.(29,39,46,63,69)
- Bacteria can also enhance the toxicity of certain drugs to normal tissues, worsening side effects and further promoting pro-inflammatory responses.(65)
Consequently, understanding the interactions between bacteria and cancer therapies has become an important area of research for improving treatment outcomes.
Ongoing Research
Ongoing research is exploring how intratumoral and intracellular bacteria may interact with cancer cells, potentially influencing inflammation, DNA interactions, and cellular pathways that could impact cancer progression and treatment responses. These factors differ for each type of cancer and each type of bacteria, which means we have only scraped the surface.
Given bacteria’s potential role in drug resistance, there is increased interest in combining antibiotics with anti-cancer treatments. However, antibiotics’ lack of specificity to intratumoral or intracellular bacteria poses a challenge, as their broad-spectrum action can disrupt the patient’s gut microbiota, which can influence the efficacy of immune checkpoint inhibitors and chemotherapy.(35,38,41)
A recent mouse study overcame this hurdle by combining anti-cancer and antibiotic treatments into a nanoparticle formulation selective for cancer cells which restored anti-tumor immune surveillance and reduced cancer relapse.(65)
Because of bacteria’s preference for tumor microenvironments, identifying unique microbial signatures from bacteria could be used as diagnostic and prognostic biomarkers for cancer screening or predictions of cancer metastasis. Ongoing studies are currently exploring this idea in lung, oral, esophageal, and colorectal cancer.(27,42,70)
Scientists are also investigating the use of bacteria as potential drug or gene delivery vehicles, taking advantage of their ability to specifically target tumors.(60) Certain bacteria, such as Salmonella and Listeria, have already shown potential as anti-tumor agents in preclinical studies and clinical trials.(50,52,64) The bacteria could be engineered to deliver tumor-suppressor genes, anti-angiogenic genes (which inhibit blood vessel formation), or other therapeutic agents directly to the tumor site.(36,44,52,60)
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Key Takeaways
The emerging role of intratumoral and intracellular bacteria in cancer biology marks a significant shift in how we understand tumorigenesis and cancer treatment. These microorganisms, once overlooked, are now recognized as significant contributors to cancer. Key takeaways from this article include:
- Intratumoral and intracellular bacteria may play a role in cancer progression and metastasis, potentially influencing tumor environments, immune responses, and cell behavior.
- Intratumoral and intracellular bacteria can alter therapeutic response and contribute to therapeutic resistance in cancer therapies, interfering with chemotherapy and immunotherapy, leading to drug resistance, relapse, and heightened toxicity in cancer treatments.
- Ongoing research is dedicated to understanding the role bacteria play in cancer treatment.
As research continues to unravel the intricate relationships between bacteria and cancer cells, new opportunities may arise for microbial-based diagnostics and therapies. Future research holds promise for transforming cancer care and enhancing patient outcomes.
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