Commensal Microbiota in Cancer Development and Therapy
Mohamed Hassan1, Abdelouahid El-Khattouti1, Ritesh Tandon4, and Christian R. Gomez1,2,3*
1Department Cancer Institute, University of Mississippi Cancer Institute, USA
2Department of Pathology, University of Mississippi Cancer Institute, USA
3Department of Radiation Oncology, University of Mississippi Cancer Institute, USA
4Department of Microbiology, University of Mississippi Cancer Institute, USA

Microbiota; Inflammation; Oncogenesis; Probiotics; Lactic acid bacteria
Human microbiota is a collective term that refers to the group of microbes including bacteria, fungi, parasites and viruses colonizing the human body. These microorganisms commonly reside on the epithelial surfaces of gastro-intestinal tract, lung, skin and oral mucosa in a symbiotic relationship with the host [1]. Different parts of the body vary in composition and characteristics of the local microbe population and these populations can fluctuate based on the physiological or pathological state of the body. Human microbiota has mostly been viewed as a beneficial factor enhancing host defense and immunity to pathogenic microorganisms; however its role as a causal agent or contributor to disease as well as in modulating the therapeutic response is starting to be understood [2,3]. Because of the ever increasingly avalanche on information acknowledging that microbiota influences the health of the host, it has become evident its influence on luminal diseases including cancer [4]. The focus of our perspective is to provide an overview of the current understanding of the role of microbiota in cancer development. In addition, we want to provide understanding on the basis for microbiota-based therapeutic options for treating tumors.
The composition of microbiota is thought to reflect symbiotic relationship between host and microbes to achieve a balanced, mutually beneficial state. Although the nature of that association is clear, the contribution of microbiota in tumor development and prevention are speculative. Current knowledge, however, points out to the relevance of mechanisms mediated by infection-driven inflammation in triggering a considerable portion of human tumors [4]. Although the role of microbiota in tumor development has been presumed since the discovery of immune cell infiltration in tumor cells by Rodolf Virchow [5], the mechanisms whereby microbiota mediates tumor initiation and progression are not completely defined. Generally, the infection with bacteria is not limited to the immune regulation, but also can trigger local and systematic inflammation. Thus, the initiation of oncogenesis can result from microbiota- induced chronic inflammation as well as infection-mediated immune dysregulation. In support of this mechanism the role of microbiota in inflammation and tumor development in the gut has been recently demonstrated [6,7]. Disrupted host-microbiota interactions in oncogenesis can be traced to other tissues and moreover be dependent on the organ-specific microbiota. Numerous examples illustrating this concept include infection with Helicobacter pylori in the development of gastrointestinal cancer; chronic infection with hepatitis B virus (HBV) and hepatitis c virus (HCV), linked to the development of hepatocellular carcinoma (HCC); infection with Chlamydia pneumonia, related to the development of lung cancer; and infection with Haemophilus influenza and Candida albicans, associated with the development of lower respiratory tract malignancies. [8,9].
The cellular and molecular mechanisms of microbiota-mediated carcinogenesis depend, in great part, on the pattern of the microbiota-host interaction. Several studies have shown that some types of bacteria are able to stimulate inflammatory mediators [10], produce toxins leading to disruption of the cell cycle control and affect cell growth [11], inhibit apoptosis [12] or promote the production of potentially carcinogenic factors [13,14]. These multiple factors act independently or interact to contribute to the tumorigenic process. Unraveling the nature of these complex mechanisms will provide basic understanding as well as novel anticancer strategies based on the host-microbiota interaction. The manipulation of microbiota to enhance its beneficial roles is considered a promising therapeutic strategy for different diseases including tumor [2-15]. For instance, microbiota represents a rich repository of metabolites that can be exploited for therapeutic benefit. Examples include probiotics, defined as viable microorganisms with beneficial physiologic or therapeutic activities [16]. Traditionally, probiotics derived from cultured foods, particularly, milk products, include beneficial microflora such as the lactic acid bacilli, Lactobacillus, and Bifidobacterium, and the non-pathogenic Escherichia coli [17]. Besides their important role in tumor initiation and promotion, specific components of the microflora can provide health benefits including immune stimulation of lymphoid tissues [18,19]. Lactic acid bacterium (LAB), a member of probiotics, has beneficial effects on the gastrointestinal microflora [20]. LAB competes with other bacteria by the production of inhibitory compounds such as organic acids, hydrogen peroxide, bacteriocines, and reutrin. The anticancer effect of LAB is mediated by the alteration of the microbiota of interest via mechanisms leading to antimutagenic effects and reduction of harmful bacteria [21]. The ability of LAB to prevent or to decrease growth and colonization of Helicobacter pylori has been reported [21]. Also, in vitro analysis of the peptidoglycan and cytoplasm fractions, and heat killed whole-cell fraction of LAB exhibited significant antiproliferative activities in several cancer cell lines [22]. Although the ability of LAB to inhibit different cancer types, the molecular mechanisms whereby LAB mediate their anticancer effects still remain to be investigated in detail. The understanding of the molecular mechanisms of probiotics, particularly, LAB-mediated anticancer effects may contribute to significant improvement in the course of cancer therapy.
In addition to its role in the development of cancer, microbiota offers an exciting opportunity for cancer treatment. The positive outcomes derived from in vivo and molecular studies directed the attention of the clinician and researcher to the area of microbiota in tumor therapy. The molecular genetic manipulation of microbiota and the exciting recent advances driven by mega projects such as the Human Microbiome Project [23] and MetaHIT [24] are facilitating improved understanding of host-microbe dialogue in health and in several ailments, including tumor disease. One outcome of our times will be the elucidation of the molecular mechanisms of host-microbial interactions, and the subsequent development of relevant therapeutic approaches for clinical application [25]. Although the current clinical support is weak, therapeutic manipulation of microbiota has promising potential as a physiologic nontoxic approach for tumor treatment. More importantly, microbiota holds the promise to maintain medically or surgically induced tumor remission; and finally stand as a valid option for the prevention of the breakout of the disease in high-risk individuals. Probiotics may be an optional for tumor treatment because of their physiologic nature and lack of obvious toxicity. Similarly, the development of microbiota based therapeutic approaches may be highly amenable for life- long use to prevent recurrence in patients with advanced tumor once remission occurs. The reliability of the microbiota as tumor therapeutic approach will depend on a clear understanding of which individual probiotic approach is indicated for a defined patient subset.
Mrs. Tara Craft is acknowledged by editorial support.
Funding acknowledgments
This study was supported by a grant from German Research Foundation (HA 5081/3–1), German cancer foundation (10-2202-Ha1) and from L'Alsace contre le cancer, France to M. Hassan; New Investigator Award Prostate Cancer Research Program from Department of Defense USA PC094680 and Prostate Cancer Foundation Creativity Award to C. Gomez. Intramural research support award from University of Mississippi Medical Center to Ritesh Tandon.

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Cite this article: Hassan M, El-Khattouti A, Tandon R, Gomez CR (2013) Commensal Microbiota in Cancer Development and Therapy. JSM Microbiology 1(1): 1002.
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