Regulation of cancer stem cells by the tumor microenvironment
Open Access
- Author:
- Wokpetah, Joseph Mawumenyo
- Graduate Program:
- Chemical Engineering
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- February 27, 2014
- Committee Members:
- Esther Winter Gomez, Thesis Advisor/Co-Advisor
- Keywords:
- Epithelial to mesenchymal transition
metastasis
transforming growth factor beta
Young's modulus
upregulation
downregulation - Abstract:
- Cancer is the abnormal growth of cells that tend to multiply in an uncontrolled way and, in some cases, metastasize to other locations in the body. According to the American Cancer Society the projected number of cancer deaths worldwide, in developed and undeveloped countries from 2008 through 2030 is on the rise and an attempt to prevent this serves as a great motivation for cancer research. Tumors are composed of a heterogeneous population of cells surrounded by a dynamic microenvironment. Cancer stem cells (CSCs), a subpopulation of cells within a tumor, are believed to be the main initiators of tumors and are thought to drive tumor growth and recurrence. CSCs are also resistant to chemotherapeutics and other advanced cancer treatments; as a result, current cancer therapies may be futile due to survival of CSCs that have the potential to initiate the formation of new tumors. Here, we sought to understand how properties of the tumor microenvironment regulate CSC qualities. We find that the rigidity of the microenvironment is a critical determinant of CSC phenotype. Transforming growth factor (TGF)-β1 induced epithelial-mesenchymal transition (EMT) in human mammary epithelial cells (HMECs), HCC 1954, and MDA-MB-231 cells cultured on substrata comparable to that of the average mammary tumor. TGFβ1 also generated an increase in cells with cancer stem cells properties. Quantitative real time PCR reveals an increase in mRNA levels of the transcription factors snail, slug, twist and FOXC2 upon treatment with TGFβ1 in cells cultured on rigid microenvironment comparable to that of the average breast tumor. These transcription factors link EMT to stemness in HMECs. Results from these studies may suggest therapeutic approaches for reducing the population of CSCs within tumors and for improving the efficacy of cancer treatments.