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Abstract Cancer accounts for a significant proportion of deaths worldwide. Cancer patients are most likely to be treated successfully when they are diagnosed at the early stages of the disease through traditional treatments such as surgery,chemotherapy and radiotherapy. However, many cancer patients are diagnosed at late stages where the cancer has become progressive and metastasized to other organs. Even if the cancer is treated at the early stages, minimal residual cells could remain dormant post-treatment and may cause tumor relapse later on where the cancer became more aggressive and eventually metastasized to other organs. Cancer is one of the leading causes of morbidity and mortality worldwide. According to the GLOBOCAN estimates of cancer incidence and mortality which is generated by the International Agency for Research on Cancer, there are an estimated 18.1 million new cancer cases in the year 2018. (Bray et al., 2018). The common therapeutic strategies used mainly in the treatment of cancer patients are surgery, radiotherapy, and chemotherapy. Cancer heterogeneity is one of the reasons of poor prognosis in cancer patients treated by these strategies (Pandya et al., 2016). Cancer is caused by the accumulation of genetic alterations, which lead to the activation or increase of proteins that promote cell growth and survival and the loss or inactivation of proteins that promote cell cycle arrest or cell death (Bruttel and Wischhusen, 2014). Many molecular lesions occur every day, most of these are repaired instantly which means that highly effective control mechanisms must be present to prevent tumors formation by mutant cells. This comprises both cellintrinsic mechanisms, such as tumor suppressor genes and DNA repair enzymes and the cell-extrinsic mechanisms of the immune system (Bruttel and Wischhusen, 2014). Tumor progression involves complicated cellular and molecular processes that are preceded by genetic or epigenetic changes leading to the transformation to cancer cells. Theoretically, carcinogenesis can be divided Chapter II Review of Literature 5 into the following stages: initiation, promotion, progression and metastasis. These stages are associated with many complex and dynamic cellular events as summarized in Figure 2.1 (Ayob and Ramasamy, 2018). Initiation encompasses the alteration or mutation of genes generated spontaneously or induced by the exposure to a carcinogen. Genetic alterations can lead to dysregulation of many biochemical signaling pathways that are associated with proliferation, differentiation, and survival. This can be affected by many factors, including the type and rate of carcinogen metabolism and the DNA repair responses (Siddiqui et al., 2015). The promotion stage is regarded as a relatively long and reversible process in which the accumulation of actively proliferating pre-neoplastic cells occur. During this period, this stage could be altered by chemopreventive agents which could affect the tumor growth rate (Ayob and Ramasamy, 2018). Progression is the stage between a pre-malignant lesion and the development of an invasive cancer (Moolgavkar and Luebeck, 2003). It is the last stage of neoplastic transformation in which genetic and phenotypic modifications as well as cellular proliferation occur. During this stage, a fast increase in the tumor size, where cells may undergo additional mutations with metastatic potential. Chemo-preventive agents act preferentially within both initiation and promotion stages of carcinogenesis (Siddiqui et al., 2015). The metastatic stage of carcinogenesis involves the migration of cancer cells from the primary tumor site to other body sites through the bloodstream or the lymphatic system (Bregenzer et al., 2019). |