Role of tumor microenvironment in maintaining cancer stem cell properties

Abstract

Cancer is a multi-stage complex disease involving a cumulative series of gene-environmental interactions leading to dysfunction in multiple mechanisms including machinery for DNA repair, apoptotic and immune responses. Most solid tumors exhibit a significant degree of phenotypic and functional heterogeneity at the population level. Despite major advancements in the diagnosis and treatment of at least some forms of cancer, the resistance of cancer cells to chemotherapy is a heavy burden for patients as it contributes to recurrence and tumor relapses. For example, while surgical resection is the most effective treatment for solid tumors, postoperative chemotherapy is minimally effective and often the residual presence of a drug-resistant stem-like cell population has led to tumor relapse (Morrison et al., 2010; Stillwell et al., 2011). Such cells, typically known as cancer stem cells (CSCs), are a primitive cell type capable of self-renewal, differentiation, and residing at the core of the cellular hierarchy within the heterogeneous tumor population (Gupta et al., 2009a; Singh et al., 2015). CSCs in solid tumors are thought to lead to drug resistance to traditional chemotherapeutics and, due to their accumulation during treatment, tumors ultimately recur and metastasize, so the discovery of selective therapeutic agents against these cells is very important. (Al Saleh et al., 2011; Clarke et al., 2006; Dean et al., 2005). Both the CSCs and normal stem cells display the similarity between their cell division and the nature of differentiation. CSCs like the normal stem cells also capable of dividing through self renewable cell division which makes them tumorigenic. This similarity between the CSCs and normal stem cells makes it difficult for selectively targeting of the CSCs. Signals from the surrounding niche or microenvironment play an important role in regulating the self-renewal of the stem cells during normal development. The altered reorganization of these niches has been known for aberrant signals leading to the deregulation of the self-renewal of stem cells and could cause carcinogenesis (Scadden DT et al., 2006). This different nature of the surrounding microenvironment between the normal stem cells and CSCs triggers niche selective cellular CHAPTER I Introduction 2 signaling that is unique to their respective cells. It is necessary to identify niche-specific signaling pathways to selectively target the CSCs without causing any harm to the normal stem cell. The hypoxic tumor microenvironment and anchorage independent growth is the distinctive feature of most of the CSCs that makes them highly metastatic. (Graeber TG et al., 1996). CSCs can survive against the stress generated by anchorage independent growth due to their inherent capability to handle the environmental stress through an important mechanism known as endoplasmic reticulum stress induce UPR signaling. There are mainly three UPR arms which decide whether cell remains to survive or die in stress condition (Wu MJ et al., 2010), so in our work, we have studied these UPR signaling in CSCs to find their selectivity for the growth of CSCs by using 3D spheroid as a model system that mimics in-vivo tumor microenvironment.