Abstract
Cancer is one of the most frequent and devastating diseases. Previous reports have shown that radio and chemo-resistant cancer stem cell (CSC) population is primarily responsible for cancer recurrences after radiotherapy and chemotherapy. Other studies demonstrated that Lissencephaly-1 (LIS1) protein, also known as platelet activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1), a dynein-binding protein involved in neural stem cell division, plays a crucial role in maintaining CSC population in hematological malignancies. Moreover, one recent report demonstrated that LIS1 gene is preferentially expressed in CD133+ glioblastoma cells and may have also an important role in regulating CD133+ CSC in glioblastoma. The hypothesis of this paper is that LIS1 plays a key role in maintaining CD133+ CSC population in various solid cancers by orientating the cell division plane through an interaction with dynein and therefore controlling the stem cell fate regulatory mechanism. As CD133+ CSC population is responsible for radio- and chemo-resistance, which finally determines the cancer recurrences and metastases, identifying the molecular mechanisms which regulate the CD133+ CSC population represents a major target for cancer research. Given the structure of LIS1, which contains WD40 repeat domain, small peptide inhibitors could be used to alter its function. Therefore, the impact of confirming this hypothesis is significant because LIS1 may become an important molecular target for future adjuvant anticancer therapies directed against radio- and chemo-resistant CSC population.
Highlights
Cancer is one of the most frequent and devastating diseases
New evidence suggests that the self-renewal of cancer stem cell (CSC) in hematological malignancies is dependent on a molecular mechanism controlled by LIS1 protein [4] and some polymorphic variants of the LIS1 gene have an increased risk for acute myeloid leukemia [5]
It is notable that there is a controversy regarding the value of CD133+ as a CSC marker, we demonstrated that in glioblastoma, LIS1 expression is up-regulated in CD133+ cells, suggesting, along with other authors, that CD133 maintains its value as reliable marker of CSC [16]
Summary
Cancer is one of the most frequent and devastating diseases. Death occurs in most cases due to systemic progression of the primary tumor after surgical and oncologic treatment (radiotherapy and chemotherapy). Previous studies revealed an important role of CD133+ tumor cells in oncogenesis and development of chemo- and radioresistance in melanoma [19] and glioblastoma [2] All these studies, unequivocally, demonstrated that CD133+ cancer cells are resistant to radio- and chemotherapy, but the mechanism of maintaining the stem like properties are not evaluated. The final result would be similar to silencing LIS1 expression, namely a significantly decreased CSC population that would increase the tumor response to radioand chemotherapy (Figure 1B) To verify this hypothesis, it is necessary to evaluate the expression and function of LIS1 in CD133+ CSC isolated from the most frequent solid cancers: breast cancer, lung cancer, colorectal cancer and melanoma. It is important to target LIS1 in the tumor cell population using a targeted/local delivery system
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