Epithelial-to-mesenchymal transition and the cancer stem cell phenotype: insights from cancer biology with therapeutic implications for colorectal cancer

Abstract

Although mortality from colorectal cancer (CRC) is decreasing, CRC is still the second highest cause of cancer-related deaths in America. Chemotherapy and radiation therapy now have central roles in our strategies to fight cancer, although we continue to lack novel strategies overcoming therapeutic resistance. Molecular mechanisms of therapeutic resistance in CRC continue to be under intense investigation. In this review, we highlight the recent evidence linking epithelial-to-mesenchymal transition (EMT) with aggressive tumor biology as well as with the cancer stem cells (CSCs) across multiple organ systems including colon cancer. Furthermore, in the era of neo-adjuvant treatment, the clinical implications are concerning that our treatments may have the potential to induce more aggressive cancer cells through EMT, perhaps even generating CSCs more capable of metastasis and further resistant to treatment. This concern and potential reality highlights the critical need for further understanding the impact of clinical therapy on the pathobiology of cancer and further supports the need to therapeutically target the CSC. Besides serving as potential biomarkers for aggressive tumor biology and therapeutic resistance, EMT and CSC molecular pathways may highlight novel therapeutic targets as strategies for improving the response to conventional anti-neoplastic agents translating into improved oncologic outcomes.

Figure 1. EMT pathways deregulated in cancer and the downstream effects

The diagram demonstrates the variety of effector pathways for EMT as well as the downstream consequences related to activation of the classic EMT transcriptional mediators. Abbreviations: TGF-b: transforming growth factor beta; EGF: Epidermal growth factor; HGF; hepatocyte growth factor; FGF: fibroblast growth factor; MMP: Matrix metalloproteinase; BID: BH3 interacting-domain.

Figure 2. Cancer stem cell therapeutic rationale

The upper pathway demonstrates the failure of conventional therapy in the presence of cancer stem cells that are resistant to therapy with subsequence tumor regrowth. The lower pathway demonstrates the potential of successful stem cell therapy resulting in a durable clinical response. Abbreviation: cancer stem cell (CSC)

Figure 3. The negative feedback loop between transcriptional mediators of cancer stem cells and EMT with the miR200 family

The diagram demonstrates the growing understanding of the complex pathways involved in miRNA signaling specifically highlighting the negative feedback loop between miRNA-200 family, EMT, and CSC mediators. Abbreviations: BMI-1: B lymphoma Mo-MLV insertion region 1 homolog; Sox-2: sex determining region Y)-box 2; KLF-4: Kruppel-like factor 4.