3. Microbiota and cancer

1. Introduction

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considered:

"Coley's toxin," as a treatment for cancer.

2. Microbiota, health and diseases

number of pathologies.

treatment of pancreatic cancer with Listeria monocytogenes [1].

• The interactions between microbiota and cancer progression. • The influence of the microbiota on the chemotherapy response.

• The microbiota imbalance influences drugs bioavailability, efficacy and toxicity.

inflammatory bowel disease, obesity, type 2 diabetes, autism, and allergies.

dences that microbiota influences the pathogenesis of IBD [2].

Microbiota affects many physiological processes, while its alteration is thought to render a

The growing evidence regarding the importance of the microbiome for health and disease and the host-microbe symbiosis at the immunological and metabolic levels become highly challenging for a better understanding of immunopathologies such as autoimmune and inflammatory disorders. Microbiome changes were correlated with a variety of diseases such as

Crohn's disease (CD) and ulcerative colitis (UC) are the most prevalent forms of inflammatory bowel disease (IBD), characterized by chronic relapsing inflammation affecting the intestinal mucosa. The etiology of these diseases is unknown, but there are increasing scientific evi-

Patients exhibit a decrease in microbial population and functional diversity, with a decrease of Firmicutes, an increase in Bacteroidetes, and facultative anaerobes such as Enterobacteriaceae [3–5]. The intestinal microbiota was also implicated in several other gastrointestinal-related diseases, such as obesity, type 2 diabetes, celiac disease, and colorectal cancer. The last two of these were

The relationship between cancer and microbiota was recognized and challenged since the nineteenth century when William Coley, a surgical oncologist, developed a mixture consisting of killed bacteria of species Streptococcus pyogenes and Serratia marcescens, also known as

Ever since, experimental and clinical researchers tried to isolate microbial agents or products to treat malignant disease, such as treatment of superficial bladder cancer based on an attenuated form of Mycobacterium bovis, an oncolytic herpes virus for the treatment of melanoma, or the

The present chapter reviews the interplay between microbiota, immune system, and anticancer therapy. The published researches in this field showed that microbiota has immunomodulatory effect on the anticancer immune response, both in the presence and in the absence of the chemotherapy. Animal and human studies evoked that the anticancer response depends on microbiota variability. In initiating an efficient chemotherapy, the following aspects should be

> Microbial communities inhabiting human body represent so far unknown environmental factors that seem to have a role in carcinogenesis.

> Cancer susceptibility, development, and progression result from a complex interplay between gene regulation and the environment.

> For decades, the researches on the interaction of the microbes with human organism were focused almost exclusively on the effects of the single pathogenic microbial infection.

> Several mechanisms regarding the cancer development were described for some microbial species.

> The direct carcinogen class usually comprises viruses which may produce cancer by genetic mechanisms [17, 18].

> Researches on molecular mechanisms revealed that most of the oncoproteins encoded by human viruses target generally the tumor suppressor proteins: retinoblastoma RB1 and p53, which play major roles in cellular anticancer protection.

> Other targets reported for carcinogenesis induce by viruses involved interaction with complex pathways of interferon signaling, transcription factors like nuclear factor-κB (NF-κB), telomerase complex, or cell adhesion molecules.

> The Epstein-Barr virus (EBV), hepatitis C virus, and human papilloma virus are only a few examples of the most studied oncogenic viruses.

> The Epstein-Barr virus (EBV) or human herpes virus 4 (HHV-4) is one of the most common viruses in humans and also the first discovered to be involved in tumorigenesis. The EBV

infects immune system cells (lymphocyte B) and epithelial cells, and the infections were correlated with some lymphoma, gastric cancer, anogenital and oropharyngeal carcinomas and with certain autoimmune diseases [19].

Hepatitis C virus is one of the major etiologic agents of hepatocellular carcinoma [20]. Researches on HCV-specific proteins revealed that they exert multiple functions during the life cycle of the virus. Due to their ability to adopt different structural conformations, the viral proteins are capable of various interactions with cellular proteins interfering in signaling pathways essential to cell functions. HCV causes genome instability suggesting that cooperation of both viral and host factors plays a role in developing the disease [21, 22].

Human papillomavirus (HPV) belongs to the DNA class viruses and is capable to infect keratinocytes of the skin and the mucosa. There are over 170 types of HPV described, and about dozen types are considered high-risk human carcinogen producing at least six types of cancer: cervix, penis, vulva, vagina, anus, and oropharynx [23].

The E6 and E7 genes of HPV have been identified as oncogenes involved in promoting tumor growth and transformation to malignancy. The E6 protein is involved in ubiquitination of p53, marking this protein for proteasomal degradation, while the protein E7 is involved in competing the retinoblastoma protein for binding and favors the cell cycle to continue.

The E6 and E7 deregulate the host innate immune defense required for the recruitment of the effector immune cells. Both proteins cooperate for the downregulation of the proinflammatory interleukins: IL-18 and IL-8 and of some chemoattractants like MCP-1 and MIP3α. Also, proteins E6 and E7 interfere in the intracellular signaling pathways NF-κB and interferon regulatory factors inhibiting the activation of these major antiviral transcription factors [24].

Although molecular mechanism of cancerogenesis has been explained for some pathogenic viruses, it is too simplistic to consider these microbes the only cause of tumorigenesis. Cancer is a complex multistep process which evolves over time and involves many signaling pathways and molecular interactions to generate a particular cellular phenotype.

Indirect carcinogen mechanisms comprise the injury of the epithelial barrier or inflammation associated to some infections produced by bacterial species like Helicobacter pylori or Chlamydia trachomatis.

Helicobacter pylori is a gram-negative pathogen which infects about half of humans all over the world and represents the main cause for gastric cancer. The H. pylori virulence factors, vacuolating cytotoxin (VacA) and CagA protein encoded by cytotoxin-associated gene-pathogenicity island, are identified as major antigens. These microbial proteins interact with several host receptors like toll-like receptor 2 (TLR2), NOD-like receptor family member NLRP3, and caspase-1 promoting the activation of the inflammasome.

The host cellular dysfunctions on secretory system, apoptosis, and immune inhibition were other mechanisms described as consequences of the H. pylori infection [25].

Chlamydia trachomatis infects both men and women, but it is commonly found in the reproductive system of women. The chronic infection causes pelvic inflammation with severe consequences like infertility. The incidence of infections is significant among patients with cervical cancer, but no proof exists to demonstrate that Chlamydia itself promotes cancer. Research proved that a common association with HPV favors cancer growth. Further studies in this direction are necessary for confirmation.

infects immune system cells (lymphocyte B) and epithelial cells, and the infections were correlated with some lymphoma, gastric cancer, anogenital and oropharyngeal carcinomas

Hepatitis C virus is one of the major etiologic agents of hepatocellular carcinoma [20]. Researches on HCV-specific proteins revealed that they exert multiple functions during the life cycle of the virus. Due to their ability to adopt different structural conformations, the viral proteins are capable of various interactions with cellular proteins interfering in signaling pathways essential to cell functions. HCV causes genome instability suggesting that coopera-

Human papillomavirus (HPV) belongs to the DNA class viruses and is capable to infect keratinocytes of the skin and the mucosa. There are over 170 types of HPV described, and about dozen types are considered high-risk human carcinogen producing at least six types of

The E6 and E7 genes of HPV have been identified as oncogenes involved in promoting tumor growth and transformation to malignancy. The E6 protein is involved in ubiquitination of p53, marking this protein for proteasomal degradation, while the protein E7 is involved in competing the retinoblastoma protein for binding and favors the cell cycle

The E6 and E7 deregulate the host innate immune defense required for the recruitment of the effector immune cells. Both proteins cooperate for the downregulation of the proinflammatory interleukins: IL-18 and IL-8 and of some chemoattractants like MCP-1 and MIP3α. Also, proteins E6 and E7 interfere in the intracellular signaling pathways NF-κB and interferon regulatory factors inhibiting the activation of these major antiviral transcription

Although molecular mechanism of cancerogenesis has been explained for some pathogenic viruses, it is too simplistic to consider these microbes the only cause of tumorigenesis. Cancer is a complex multistep process which evolves over time and involves many signaling

Indirect carcinogen mechanisms comprise the injury of the epithelial barrier or inflammation associated to some infections produced by bacterial species like Helicobacter pylori or Chlamydia

Helicobacter pylori is a gram-negative pathogen which infects about half of humans all over the world and represents the main cause for gastric cancer. The H. pylori virulence factors, vacuolating cytotoxin (VacA) and CagA protein encoded by cytotoxin-associated gene-pathogenicity island, are identified as major antigens. These microbial proteins interact with several host receptors like toll-like receptor 2 (TLR2), NOD-like receptor family member NLRP3, and

The host cellular dysfunctions on secretory system, apoptosis, and immune inhibition were

other mechanisms described as consequences of the H. pylori infection [25].

pathways and molecular interactions to generate a particular cellular phenotype.

caspase-1 promoting the activation of the inflammasome.

tion of both viral and host factors plays a role in developing the disease [21, 22].

cancer: cervix, penis, vulva, vagina, anus, and oropharynx [23].

and with certain autoimmune diseases [19].

124 Anti-cancer Drugs - Nature, Synthesis and Cell

to continue.

factors [24].

trachomatis.

Other experiments indicate a correlation between some commensals, the production of oxygen-reactive species, and colon cancer. Thus, superoxide-producing Enterococcus faecalis was demonstrated to cause colonic epithelial cell DNA damage [26].

Recent years' researches focused on obesity as a risk factor for different types of cancer. Gut microbiota plays an important role in developing obesity. Some Clostridium spp. are microorganisms overrepresented in obese intestine and were directly correlated with liver and colorectal cancers. These commensals convert primary bile acids into deoxycholic acid (DCA), a carcinogen that can cause DNA damage via the production of free radicals [27].

For a long time, scientific research describes many other potential microorganisms involved in cancer promoting, but several questions about the main cause of tumorigenesis were raised because of a low incidence of cancer among infected patients with susceptible agents.

Recent researches have changed the perspective on many human diseases. Many scientific publications in the last years sustain the fact that global changes in our microbiome are the main causes of disease and not only a single opportunistic pathogen development.

Increased communities of Capnocytophaga gingivalis, Capnocytophaga ochracea, Eubacterium sabureum, Leptotrichia buccalis, and Streptococcus mitis present in saliva were observed in patients with oral squamous cell carcinoma.

Human esophageal cancer was associated in some cases with an increased presence of Streptococcus anginosus, Streptococcus mitis, Treponema denticola, or some Campylobacter spp.

Salmonella typhi and S. paratyphi were increased in some bile samples collected from patients with gall bladder cancer.

Colorectal cancer is one of the most studied regarding the microbial imbalance and molecular mechanisms of the disease.

Cohort studies demonstrated that samples collected from patients with colon cancer presented feces bacterial diversity with increased communities of pro-inflammatory species of Fusobacterium and Porphyromonas and a decreased presence of Lactobacillus, Microbacterium, Anoxybacillus, and Akkermansia muciniphila.

In colon cancer cases induced by a preexisting inflammatory colitis, microbiota played an important role in influencing inflammation or innate immunity, genomic stability of intestinal epithelial cells (IECs), or the release of some metabolites functioning as histone deacetylase inhibitors. Studies performed in gnotobiotic or in antibiotic-treated mice revealed the implication of microbes in tumorigenesis driven or not by inflammation.
