Tumor Heterogeneity Part 1: Cancer Stem Cells

Anke Wang

Rensselaer Polytechnic Institute

Publication Date: January 1, 2015

While tumors are often thought of merely homogenous masses of cells, research states that is an out-of-date model of tumor physiology. In most cases, tumors originate from a single cell. Yet, when clinical diagnosis occurs, cells from the same tumor mass display a wide variety of different features, including proliferation potential, which can play a role in the effectiveness of treatment (Marusyk and Kornelia, 2010). Currently, there are two models used to explain the heterogeneity tumors display: Cancer stem cell and Clonal evolution (Shackleton, et al., 2009).

With the cancer stem cell model of tumors, not all cells are capable of forming tumors. Only a small subset of cells, the cancer stem cells have the capability to maintain the tumor (Clarke, et al., 2006). These cells are capable of continuous growth, unrestricted by the Hayflick Limit that constrains differentiated cells. With this model, only a small fraction of the tumor, the cancer stem cells, are responsible for both the metastasis and the relapse in cancer patients. Currently, cancer stem cells have been isolated and identified in a variety of cancers, including leukemia, brain, breast, colon, and a more. In an in vivo models, immunodeficient mice were transplanted with acute myeloid leukemia cells and only cells expressing a CD34+/CD38- phenotype initiated leukemia. On the other hand leukemic cells without that phenotype were unable to initiate leukemia in these mice (Bjerkvig, et al., 2005). In such transplants, cancer stem cells create tumors that are comprised of both cancer stem cells and differentiated cells that comprise the mass of the tumor.

While cancer stem cells have been identified and isolated through strategies similar to that of non-cancerous stem cells due to some similarities between the two types of cells(Glebiewska, et al., 2011), there has been no definitively known origin of cancer stem cells. Currently there are several hypothesis within the scientific community as to the origin, and more than one may be the correct answer depending on the phenotype of the tumor and the type of tumor.

Some researchers hypothesize that cancer stem cells are generated by stem cell populations during development (Wang, et al., 2009). These mutated cells then give rise to more cells with the same mutation, thereby increasing the risk that the mutation can cause cancer.

Another hypothesis follows along the same line, but instead of stem cells during development, adult stem cells mutate and become cancer stem cells (Clarke, et al., 2006). Essentially, when adult stem cells have to divide and differentiate, mutations occur in the DNA and is not corrected. These mistakes are passed onto daughter cells, both the stem cell variety and the differentiated cells, creating a tumor that is possibly cancerous.

A third hypothesis raises questions about the ability of a mutated cell to become undifferentiated and regain some stem cell characteristics (Clarke, et al., 2006). This hypothesis offers an alternative to pinpoint any specific cell as the cell of origin since it suggests that any cell can become a cancer stem cell and create cancerous tumors. A different hypothesis suggests there may be several different types of cancer stem cells in the same tumor, yet only one is optimal for the specific environment with other lines becoming the optimal line in a different environment (Clarke, et al., 2006). This would allow the tumor to be able to adapt to different environments, including adapting to treatments to remove the tumor. Yet, with this model, it is extremely difficult to be able to pinpoint the origin of the cancer stem cell.

In light of these discoveries about tumor composition, especially cancerous tumors, there has been a push for a more focused cancer therapy that would address the issue of cancer stem cells. While the exact origin of cancer stem cells are still unknown, these cells are identifiable and are able to be isolated, allowing researchers to focus on learning more about them while searching for a way to prevent relapses in both cancerous and non-cancerous tumors. While tumor heterogeneity does indeed create a tougher battle against cancer especially the hypothesis with multiple cancer stem cells lines, it also helps explain some of the phenomena that cancerous tumors display which allows researchers to hone in that much more to reduce the fatality of cancer.

References:

1) Marusyk, A., Kornelia, P. (2010) Tumor heterogeneity: causes and consequences. Biochimica et Biophysica Acta, 1805 (1), 105-117.

2) Shackleton, M., Quintana, E., Fearon, E.R., Morrison, S.J. (2009). Heterogeneity in Cancer: Cancer Stem Cells versus Clonal Evolution. Cell, 138(5), 822-829.

3) Clarke, M.F., Dick, J.E., Dirks, P.B., Eaves, C.J., Jamieson, C.H.M., Jones, D.L., Visvader, J., Weissman, I.L., Wahl, G.M. (2006) Cancer Stem Cells-Perspectives on Current Status and Future Directions: AACR Workshop on Cancer Stem Cells. Cancer Research, 66(19), 9339-9344.

4) Golebiewska, A., Brons, N.H.C., Bjerkvig, R., Niclou, S.P. (2011). Critical Appraisal of the Side Population Assay in Stem Cell and Cancer Stem Cell Research. Cell Stem Cell, 8(2), 136-147.

5) Bjerkvig, R., Tysnes, B.B., Aboody, K.S., Najbauer, J., Terzis, A.J.A. (2005) The origin of the cancer stem cell: current controversies and new insights. Nature Reviews Cancer, 5, 899-904.

6) Wang, Y., Yang, J., Zheng, H., Tomasek. G.J., Zhang, P., McKeever, P.E., Lee, E.Y-H., Zhu, Y. (2009) Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell, 15(6), 514-526.

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