Cancer Stem Cells in Drug Resistance and Drug Screening: Can We Exploit the Cancer Stem Cell Paradigm in Search for New Antitumor Agents?

Abstract

It is now evident that despite an enormous progress in our understanding of molecular mechanisms and processes which operate in tumor cells, this knowledge does not directly translate into more efficient treatment and cure of cancer patients. At the origin of the inefficiency of cancer treatment is inherent or therapy-induced resistance of tumor cells to therapeutic agents. Many different mechanisms of drug resistance have been described and characterized, including elevated expression of membrane drug transporters, changed drug activation and/or detoxification, more efficient repair of drug-induced lesions and nonfunctional cell death pathways. Another reason for an inefficiency of currently available cancer treatment modalities can be related to cellular heterogeneity of tumors and targeting by anticancer drugs only some tumor cells in the population, which are more sensitive to applied therapeutic agents. In this situation, anticancer treatment can lead to the selection of drug resistant tumor cells and cytostatic rather than cytotoxic effect. The origin of these more resistant cells in tumor cell population was classically perceived as a result of spontaneous or therapy-induced gene mutations, making surviving tumor cells less sensitive to anticancer agents. According to the alternative hypothesis, heterogeneity of tumor cell population, also in its response to drug treatment, can result from a clonal expansion of rare malignant stem cells which may differentiate and produce tumors. Cancer was proposed to originate from stem cells more than 150 years ago (see Wicha et al., 2006 and references therein) and this idea re-appeared in the early sixties of the last century, first for leukemias (Bruce & van der Gaag, 1963) and later for epithelial tumors (Hamburger & Salmon, 1977). About the same time, Pierce and Wallace provided experimental evidence for the existence of cellular hierarchy in tumors, where malignant undifferentiated cells give rise to benign well-differentiated cells (Pierce & Wallace, 1971). A few years later, Potter proposed a new model of oncogenic transformation according to which tumor cells resulted from blocked differentiation of their progenitors (Potter, 1978). Collectively, a new paradigm of cancer origin was established in which malignant stem cells with de-regulated selfrenewal and differentiation mechanisms are responsible for tumor initiation and growth.