The Colon Cancer Stem Cell Microenvironment Holds Keys to Future Cancer Therapy

Abstract

Background Colorectal cancer remains the most common gastrointestinal cancer. While screening combined with effective surgical treatment has reduced its mortality, we still do not have effective means to prevent recurrence nor to treat metastatic disease. What we know about cancer biology has gone through revolutionary changes in recent decades. The advent of the cancer stem cell theory has accelerated our understanding of the cancer cell. However, there is increasing evidence that cancer cells are influenced by their surrounding microenvironment. Purpose This review divides the tumor microenvironment into four functional components—the stem cell niche, cancer stroma, immune cells, and vascular endothelia—and examines their individual and collective influence on the growth and metastasis of the colon cancer stem cell. The discussion will highlight the need to fully exploit the tumor microenvironment when designing future prognostic tools and therapies.

Cancer Stem Cells: Targeting the Roots of Cancer, Seeds of Metastasis, and Sources of Therapy Resistance

“…Ofer Reizes (Cleveland Clinic, Cleveland, OH, USA) demonstrated that leptin and leptin receptor (LEPR), a JAK/STAT cytokine receptor expressed in breast CSCs (BCSCs), are necessary for maintaining the NANOG+ BCSC phenotype (32). Dr. Emina Huang (Cleveland Clinic, Cleveland, OH, USA) showed that elevated IL-8 levels secreted from stromal fibroblasts cause a substantial increase in tumorigenicity induced by ALDH-1 + colon cancer initiating cells (CCICs) within colitis associated cancer (33). …”

Self-renewal molecular mechanisms of colorectal cancer stem cells

“…This cell population is not stationary, but can be transformed from mesenchymal cells, endothelial cells, adipose cells and even cancer epithelial cells. CAFs promote tumor progression and invasion by both mechanical forces and metabolic machinery (113). On the one hand, CAFs induce protease-mediated extracellular matrix remodeling, serving to guide the structures that direct migration (114).…”

“…In addition to the above mentioned, others, such as blood vessels, microorganisms and normal cells, all exert an influence on the micro-environment (113,138). All of these complex components interact with each other to regulate CCSC self-renewal.…”

Metaplastic Paneth Cells in Extra-Intestinal Mucosal Niche Indicate a Link to Microbiome and Inflammation

“…The IBD patients have an increased risk to develop inflammation-associated colon cancer. Additionally, during repair and regeneration of damaged epithelium in IBD patients, there might be an increased chance of mutation accumulation (cyclic hit model, described in later paragraphs), and the metaplastic Paneth cells may contribute to accelerated epithelial tumorigenesis by providing stem cell growth factor to tumor cells (Chen and Huang, 2014).…”