**3. TLRs biology in the pathogenesis of cancer**

In the host cell, TLRs are expressed either on cell membrane or in intracellular compartments (i.e. endosomes) [10]. TLRs belong to a family of pattern recognition receptors (PRRs) that are best-known for their role in host defense mechanism against a number of pathogens. Infection with potential microbial pathogens (bacteria, viruses, protozoa, and fungi) provokes innate and adaptive immune system [26]. In vertebrates, interactions between innate and adaptive immunity leads to highly efficient recognition and clearance of pathogens. Innate immune response elicits nonspecific activation of immune cells (neutrophils, monocytes, macrophages, dendritic cells (DCs), natural killer (NK) cells) and complements system [33, 34]. Inflammation is the immune system's response to protect our body against any harmful stimuli like pathogens, cell damage and harmful/toxic compound. However, uncontrolled acute inflammation may become chronic; contributing to a variety of diseases including cancer [19]. In 1858, Rudolf Virchow noticed that the site of chronic inflammation is highly susceptible to cancer development [35]. He also hypothesized that chronic inflammation could promote the proliferation of cells and thus, the development of cancer. An association between the inflammation and development of cancer has long been appreciated [33]. In 2000, Hanahan and Weinberg proposed a model to define six hallmarks of cancer progression [36]. However, emerging evidence also reiterates the role of inflammation in cancer development. Various studies have shown a close link between chronic inflammation and cancer, such as long standing *H.pylori* infection and gastric cancer [37], chronic pancreatitis and pancreatic cancer, chronic bronchitis and lung cancer, human papillomavirus (HPVs) infection mediated cervical cancer [38], and chronic cholecystitis with gall bladder cancer [33]. Besides inflammatory response, TLR signaling has been shown to regulate apoptosis through the expression of anti-apoptotic proteins or inhibitors of apoptosis [39]. TLRs regulate variety of cellular responses which include the anti-apoptotic effect of NF-κB, a transcription factor commonly engaged in inflammatory conditions [12, 14]. Although this response can be initiated by several types of PRRs, and TLRs are the best-characterized key players. TLRs also regulate cell proliferation, apoptosis, invasion, and survival by recruiting more immune cells to enhance inflammation in the tumor microenvironment [40]. These tumor cells further release proangiogenic factors and growth factors, which enhance their resistance to cytotoxic lymphocyte attack, thereby leading to immune evasion. As mentioned earlier, TLRs function as double-edged swords, with both pro- and antitumor consequences. However, up-regulation of TLRs in tumor cells may directly or indirectly contribute to carcinogenesis in different organs. Engagement of TLRs on the surface of tumor cells with their ligands can activate subsequent

signaling cascades involving cytokine and chemokine production. Subsequently, these factors can promote tumor invasion, tumor cell survival (apoptosis resistance), chemo-resistance, tumor progression and metastasis.
