Are Stem Cells Involved in Cancer? [Stem Cell Information]

Charles A. Goldthwaite, Jr., PhD.

Data from 2007 suggest that approximately 1.4 million men and women in the U.S. population are likely to be diagnosed with cancer, and approximately 566,000 American adults are likely to die from cancer in 2008.1 Data collected between 1996 and 2004 indicate that the overall 5-year survival rate for cancers from all sites, relative to the expected survival from a comparable set of people without cancer, is 65.3%.1 However, survival and recurrence rates following diagnosis vary greatly as a function of cancer type and the stage of development at diagnosis. For example, in 2000, the relative survival rate five years following diagnosis of melanoma (skin cancer) was greater than 90%; that of cancers of the brain and nervous system was 35%. Once a cancer has metastasized (or spread to secondary sites via the blood or lymph system), however, the survival rate usually declines dramatically. For example, when melanoma is diagnosed at the localized stage, 99% of people will survive more than five years, compared to 65% of those diagnosed with melanoma that has metastasized regionally and 15% of those whose melanoma has spread to distant sites.2

The term "cancer" describes a group of diseases that are characterized by uncontrolled cellular growth, cellular invasion into adjacent tissues, and the potential to metastasize if not treated at a sufficiently early stage. These cellular aberrations arise from accumulated genetic modifications, either via changes in the underlying genetic sequence or from epigenetic alterations (e.g., modifications to gene activation- or DNA-related proteins that do not affect the genetic sequence itself).3,4 Cancers may form tumors in solid organs, such as the lung, brain, or liver, or be present as malignancies in tissues such as the blood or lymph. Tumors and other structures that result from aberrant cell growth, contain heterogeneous cell populations with diverse biological characteristics and potentials. As such, a researcher sequencing all of the genes from tumor specimens of two individuals diagnosed with the same type of lung cancer will identify some consistencies along with many differences. In fact, cancerous tissues are sufficiently heterogeneous that the researcher will likely identify differences in the genetic profiles between several tissue samples from the same specimen. While some groupings of genes allow scientists to classify organ-or tissue-specific cancers into subcategories that may ultimately inform treatment and provide predictive information, the remarkable complexity of cancer biology continues to confound treatment efforts.

Once a cancer has been diagnosed, treatments vary according to cancer type and severity. Surgery, radiation therapy, and systemic treatments such as chemotherapy or hormonal therapy represent traditional approaches designed to remove or kill rapidly-dividing cancer cells. These methods have limitations in clinical use. For example, cancer surgeons may be unable to remove all of the tumor tissue due to its location or extent of spreading. Radiation and chemotherapy, on the other hand, are non-specific strategieswhile targeting rapidly-dividing cells, these treatments often destroy healthy tissue as well. Recently, several agents that target specific proteins implicated in cancer-associated molecular pathways have been developed for clinical use. These include trastuzumab, a monoclonal antibody that targets the protein HER2 in breast cancer,5 gefitinib and erlotnib, which target epidermal growth factor receptor (EGFR) in lung cancer,6 imatinib, which targets the BCR-ABL tyrosine kinase in chronic myelogenous leukemia,7 the monoclonal antibodies bevacizumab, which targets vascular endothelial growth factor in colorectal and lung cancer,8 and cetuximab and panitumumab, which target EGFR in colorectal cancer.8 These agents have shown that a targeted approach can be successful, although they are effective only in patients who feature select subclasses of these respective cancers.

All of these treatments are most successful when a cancer is localized; most fail in the metastatic setting.911 This article will discuss the CSC hypothesis and its supporting evidence and provide some perspectives on how CSCs could impact the development of future cancer therapy.

A consensus panel convened by the American Association of Cancer Research has defined a CSC as "a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor."12 It should be noted that this definition does not indicate the source of these cellsthese tumor-forming cells could hypothetically originate from stem, progenitor, or differentiated cells.13 As such, the terms "tumor-initiating cell" or "cancer-initiating cell" are sometimes used instead of "cancer stem cell" to avoid confusion. Tumors originate from the transformation of normal cells through the accumulation of genetic modifications, but it has not been established unequivocally that stem cells are the origin of all CSCs. The CSC hypothesis therefore does not imply that cancer is always caused by stem cells or that the potential application of stem cells to treat conditions such as heart disease or diabetes, as discussed in other chapters of this report, will result in tumor formation. Rather, tumor-initiating cells possess stem-like characteristics to a degree sufficient to warrant the comparison with stem cells; the observed experimental and clinical behaviors of metastatic cancer cells are highly reminiscent of the classical properties of stem cells.9

The CSC hypothesis suggests that the malignancies associated with cancer originate from a small population of stem-like, tumor-initiating cells. Although cancer researchers first isolated CSCs in 1994,14 the concept dates to the mid-19th century. In 1855, German pathologist Rudolf Virchow proposed that cancers arise from the activation of dormant, embryonic-like cells present in mature tissue.15 Virchow argued that cancer does not simply appear spontaneously; rather, cancerous cells, like their non-cancerous counterparts, must originate from other living cells. One hundred and fifty years after Virchow's observation, Lapidot and colleagues provided the first solid evidence to support the CSC hypothesis when they used cell-surface protein markers to identify a relatively rare population of stemlike cells in acute myeloid leukemia (AML).14 Present in the peripheral blood of persons with leukemia at approximately 1:250,000 cells, these cells could initiate human AML when transplanted into mice with compromised immune systems. Subsequent analysis of populations of leukemia-initiating cells from various AML subtypes indicated that the cells were relatively immature in terms of differentiation.16 In other words, the cells were "stem-like"more closely related to primitive blood-forming (hematopoietic) stem cells than to more mature, committed blood cells.

The identification of leukemia-inducing cells has fostered an intense effort to isolate and characterize CSCs in solid tumors. Stem cell-like populations have since been characterized using cell-surface protein markers in tumors of the breast,17 colon,18 brain,19 pancreas,20,21 and prostate.22,23 However, identifying markers that unequivocally characterize a population of CSCs remains challenging, even when there is evidence that putative CSCs exist in a given solid tumor type. For example, in hepatocellular carcinoma, cellular analysis suggests the presence of stem-like cells.24 Definitive markers have yet to be identified to characterize t
hese putative CSCs, although several potential candidates have been proposed recently.25,26 In other cancers in which CSCs have yet to be identified, researchers are beginning to link established stem-cell markers with malignant cancer cells. For instance, the proteins Nanog, nucleostemin, and musashi1, which are highly expressed in embryonic stem cells and are critical to maintaining those cells' pluripotency, are also highly expressed in malignant cervical epithelial cells.27 While this finding does not indicate the existence of cervical cancer CSCs, it suggests that these proteins may play roles in cervical carcinogenesis and progression.

Given the similarities between tumor-initiating cells and stem cells, researchers have sought to determine whether CSCs arise from stem cells, progenitor cells, or differentiated cells present in adult tissue. Of course, different malignancies may present different answers to this question. The issue is currently under debate,9,12 and this section will review several theories about the cellular precursors of cancer cells (see Fig. 9.1).

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Are Stem Cells Involved in Cancer? [Stem Cell Information]