Selected Aspects of Chemoresistance Mechanisms in Colorectal Carcinoma-A Focus on Epithelial-to-Mesenchymal Transition, Autophagy, and Apoptosis

Abstract

Chemoresistance has been found in all malignant tumors including colorectal carcinoma (CRC). Nowadays chemoresistance is understood as a major reason for therapy failure, with consequent tumor growth and spreading leading ultimately to the patient's premature death. The chemotherapy-related resistance of malignant colonocytes may be manifested in diverse mechanisms that may exist both prior to the onset of the therapy or after it. The ultimate function of this chemoresistance is to ensure the survival of malignant cells through continuing adaptation within an organism, therefore, the nature and spectrum of cell-survival strategies in CRC represent a highly significant target of scientific inquiry. Among these survival strategies employed by CRC cells, three unique but significantly linked phenomena stand out-epithelial-to-mesenchymal transition (EMT), autophagy, and cell death. In this mini-review, current knowledge concerning all three mechanisms including their emergence, timeline, regulation, and mutual relationships will be presented and discussed.

Keywords: apoptosis; autophagy; chemoresistance; colorectal carcinoma (CRC); epithelial-to-mesenchymal transition (EMT).

Figure 1

Development of intrinsic and acquired chemoresistance in the process of colorectal carcinogenesis. During malignant conversion, individual cells are exposed to carcinogenic events from external and internal environments, which prompt the gradual development of intrinsic chemoresistance to mediate cell survival. During advanced stages of carcinogenesis and upon exposure to chemotherapy-related stress combined with selection-adaptation-related pressures, malignant cells develop acquired chemoresistance.

Figure 2

Selected phenotype malignant colorectal carcinoma cells develop to escape chemotherapy-dependent effects. Normal colonic epithelial cells (a) undergo malignant conversion (b) and upon exposure to various stresses (environment and/or chemotherapy-related) they became resistant to cell death (CD) or upregulate autophagy (A) or undergo epithelial-mesenchymal transition (EMT) to escape (c). The resulting surviving malignant cell populations are a heterogeneous mixture of cells with the mentioned phenotypes (d).

Figure 3

The mutual relationship between autophagy, epithelial mesenchymal transition (EMT), and apoptosis as three selected chemoresistence mechanisms in malignant colorectal carcinoma (CRC) cells. Resistant CRC cells upregulate autophagy, which acts to suppress apoptosis (dotted line). Alternatively, autophagy may contribute to apoptosis of these cells (full line). EMT in CRC cells inhibits their ability to undergo apoptosis (dotted line). Autophagy and EMT appear to be mutually exclusive events in CRC cells (dashed line).