In a review article in Cancer and Metastasis Reviews Leena von Hertzen, H. Joensuu and T. Haahtela, from the Skin and Allergy Hospital, Helsinki University Central Hospital, Finland, summarize the epidemiological data related to microbial deprivation and cancer, and discuss the involvement of the T helper (Th)17/Interleukin(IL)-23 axis and the immunomodulatory potential of environmental microbiota in cancer-associated inflammation.
The cancer-inflammation link was probably first recognized by Virchow in the 1860s, and nowadays it is well accepted concept that inflammatory responses play decisive roles at different stages of tumor development.
Inflammation has been suggested to increase the risk for cancer, but microbial components may play an important role in endorsing the innate immunity and regulatory networks and might thus prevent persistent inflammation and further carcinogenesis.
Recent evidence indicates that people who live in microbe-rich environments in simple living conditions are relatively protected against asthma, allergies and some autoimmune diseases. Micro-organisms that co-evolved with man since ancient times generally do not elicit overt immune responses but rather trigger the immune regulatory network to induce regulatory cytokines.
Thus, hypothetically, cancers might occur less frequently in populations that are heavily exposed to environmental microbiota due to well functioning immunosurveillance. In fact, recent occupational studies report reduced cancer rates among populations presumably heavily exposed to environmental microbiota.
In Cancer and Metastasis Reviews L. von Hertzen, H. Joensuu and T. Haahtela discuss that Th1 immunity has traditionally been considered an important defense mechanism in immunosurveillance related to tumor development and progression. New studies however indicate that inflammation exerted by the Th17/IL-23 axis is associated with tumor progression.
The authors of this review suggest that continuous microbial exposure may be associated with 1) activation of microbial receptors on/in immune and other cells, which may have direct antitumor effect and an indirect effect by endorsing innate immunity and homeostatic mechanisms, and 2) strengthening of the regulatory network, which in turn can prevent or dampen in early phases the development of Th17 cells and inflammatory mediators, such as Cox-2 and PGE2, central to cancer-promoting inflammation. This new concept might pave a way for novel strategies for cancer prevention and therapy.
A 2022 review published in the Journal of Translational Medicine outlines the association between the microbiome and cancer development and some mechanisms involved in this process. The authors discuss the oncogenic actions of microbiota through the induction of chronic inflammation.
Thus, microorganisms contribute to tumor initiation and progression by inducing tumor-promoting inflammation or translocating to the tumor site and persisting cancer-induced inflammation. For example, some microbial species, such as Fusobacterium nucleatum have been linked to the upregulation of TNF-α (tumor necrosis factor), β-catenin, and NF-κB (nuclear factor-kappa B). Or, the induction of a shift from pro-inflammatory M1-phenotype to a tumor-promoting M2-phenotype.
Moreover, it appears that the TLR4 is upregulated in colon cancer samples from patients with chronic ulcerative colitis and contributes to the colon carcinogenesis by activating the EGFR (epidermal growth factor receptor) signalling.
In addition, recent evidence indicates that T-helper 17 and regulatory T cells are also implicated in tumorigenesis. Thus, disturbance of the microbiota balance (dysbiosis) and an increase in the abundance of Th17-inducing bacteria can cause chronic inflammation that leads to the onset and progression of cancer. Studies confirmed that tumoral inflammation driven by Th17 cells is often tumor-promoting and linked to a poor prognosis in colorectal cancer.
Activating the IL-23 signaling pathway after Toll-like receptors sense translocated microbes or microbial products, and triggering the MyD88 adaptor activation, is critical for producing downstream cytokines, i.e., IL-17. Furthermore, the production of ATP by commensal microbiota has been proposed as the mediator for naturally occurring and/or pathogenic Th17 cell differentiation in lamina propria.
Interestingly, there are specific bacterial species that promote Th17 differentiation. For instance, segmented filamentous bacteria (SFB) produces serum amyloid A (SAA), which triggers Th17 cells differentiation by acting on dendritic cells in the lamina propria. Or, colonization with enterotoxigenic Bacteroides fragilis, promotes IL-17-producing cells-driven inflammation and the development of colon cancer.
The authors also outline the carcinogenic action of microbiota through the production of toxins and metabolites. Thus, some bacterial metabolites directly contribute to the causation of cancer. For instance, the cytotoxin-associated gene A (CagA) of Helicobacter pylori, a bacterial oncoprotein linked to the development of gastric cancer by promoting the genetic instability and interactions with host cell proteins like SHP2 (Src homology two phosphatases), E-cadherin, and PAR1 (Partitioning-defective 1).
Finally, the authors also summarize some cancer-preventing properties of microbes. Probiotics’ cancer-prevention effects include (1) maintaining colon homeostasis; (2) modulating intestinal microflora composition; (3) binding and inactivating carcinogens; (4) producing anti-carcinogenic metabolites; and (5) immunomodulatory effects like phagocytes activation.
Of note, Lactobacillus and Bifidobacterium are the two most common probiotics in the digestive system. Lactobacillus prevents cancer by producing antioxidants and anti-angiogenesis factors, reducing inflammation and DNA damage, and preventing polyamines and tumor-specific antigens expression.
Cover Image credit: In the absence of sufficient microbial stimuli, immunoregulatory circuits are not induced adequately resulting in low levels of interleukin (IL)-10/transforming growth factor (TGF)-β. An inflammatory milieu, in turn, enhances the conversion of TREG cells to TH17 cells and favours the enrichment of bacteria in the gut (and other microbiota) that tolerate inflammatory mediators, creating a self-perpetuating system. Ambient air pollution might act in synergy and further strengthen immune dysregulation by inactivating FOXP3+ TREG cells by epigenetic mechanisms. Together, these factors probably contribute to the increase in inflammatory diseases in developed countries. From: Natural immunity, by Leena von Hertzen Ilkka Hanski and Tari Haahtela EMBO Reports (2011)12:1089-1093.