Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 289

These developmental pathways are also strongly implicated as stem cell regulators. Both Sonic Hedgehog (SHH) and Wnt pathways are commonly hyperactivated in tumors and are required to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are commonly expressed at high levels. A degree of crosstalk exists between the two pathways and their activation commonly goes hand-in-hand. This is a trend rather than a rule. For instance, in colon cancer, hedgehog signaling appears to antagonize Wnt. SHH blockers are available, such as cyclopamine.

The cancer stem cell hypothesis accounts for observed patterns of cancer recurrence and metastasis following an apparently successful therapeutic intervention. In clinical practice, however, some cancers prove quite aggressive and invasive, resisting chemotherapy or radiation even when administered at relatively early stages of tumor progression. These tumors have increased chances of spreading, making treatment more difficult and compromising quality of life. The presence of CSCs in some malignancies may account for some of these metastases. Some researchers have suggested that the tumor aggressiveness may correlate with the proportion of cancer stem cells within a corresponding tumor. In this scenario, less-aggressive cancers contain fewer CSCs and a greater proportion of therapy-sensitive non-CSCs.

There is also evidence to suggest that CSCs may be able to selectively resist many current cancer therapies, although this property has yet to be proven. For example, normal stem cells and metastatic cancer cells overexpress several common drug-resistance genes. As a result, breast CSCs express increased levels of several membrane proteins implicated in resistance to chemotherapy. These cells have also been shown to express signaling molecules such as Hedgehog and Bmi-1,44, which are essential for promoting self-renewal and proliferation of several types of stem cells. Moreover, experiments in cell lines from breast cancer and glioma have shown that CSCs (as identified by cell-surface markers) are more resistant to radiotherapy than their non-cancer stem cell counterparts. In the face of radiation, the CSCs appear to survive preferentially, to repair their damaged DNA more efficiently, and to begin the process of self-renewal.

These discoveries have led researchers to propose several avenues for treating cancer by targeting molecules involved in CSC renewal and proliferation pathways. Potential strategies include interfering with molecular pathways that increase drug resistance, targeting proteins that may sensitize cancer stem cells to radiation, or restraining the CSCs self-renewal capacity by modifying their cell differentiation capabilities. In each case, successful development of a therapy would require additional basic and clinical research. Researchers must characterize the CSCs associated with a given tumor type, identify relevant molecules to target, develop effective agents, and test the agents in preclinical models, such as in animals or cell lines. However, by targeting fundamental CSC cellular signaling processes, it is possible that a given treatment could be effective against multiple tumor types.

Existing cancer treatments have mostly been developed based on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals cannot provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally difficult to study. The efficacy of cancer treatments is, in the initial stages of testing, often measured by the ablation fraction of tumor mass (fractional kill). As CSCs would form a very small proportion of the tumor, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells that form the bulk of the tumor, but are unable to generate new cells. A population of CSCs that gave rise to it could remain untouched and cause a relapse of the disease. Most of the studies that have identified human CSCs have used mouse xenograft assays and cells from only a small number of human tumor samples, making it difficult to draw firm conclusions. While these tumor-initiating cells have been described as being a rare class, several studies have found that the number of cells that can form tumors in these mouse experiments is actually quite large.

Zarish Umar

Independent Scholar

See Also: Brain Cancer; Colon Cancer; Fetal Stem Cells; Lung Cancer; Skin Cancer.