Cancer Research Institute

About: Cancer Research Institute is a nonprofit organization based out in New York, New York, United States. It is known for research contribution in the topics: Cancer & Population. The organization has 1061 authors who have published 754 publications receiving 26712 citations.

Understanding the Role of Keratins 8 and 18 in Neoplastic Potential of Breast Cancer Derived Cell Lines

Abstract: Background Breast cancer is a complex disease which cannot be defined merely by clinical parameters like lymph node involvement and histological grade, or by routinely used biomarkers like estrogen receptor (ER), progesterone receptor (PGR) and epidermal growth factor receptor 2 (HER2) in diagnosis and prognosis. Breast cancer originates from the epithelial cells. Keratins (K) are cytoplasmic intermediate filament proteins of epithelial cells and changes in the expression pattern of keratins have been seen during malignant transformation in the breast. Expression of the K8/18 pair is seen in the luminal cells of the breast epithelium, and its role in prognostication of breast cancer is not well understood. Methodology/Principal Findings In this study, we have modulated K8 expression to understand the role of the K8/18 pair in three different breast epithelium derived cell lines: non-transformed MCF10A, transformed but poorly invasive MDA MB 468 and highly invasive MDA MB 435. The up-regulation of K8 in the invasive MDA MB 435 cell line resulted in a significant decrease in proliferation, motility, in-vitro invasion, tumor volume and lung metastasis. The down-regulation of K8 in MDA MB 468 resulted in a significant increase in transformation potential, motility and invasion in-vitro, while MCF10A did not show any changes in cell transformation assays. Conclusions/Significance These results indicate the role of K8/18 in modulating invasion in breast cancer -its presence correlating with less invasive phenotype and absence correlating with highly invasive, dedifferentiated phenotype. These data may have important implications for prognostication of breast cancer.

Radiation-induced homotypic cell fusions of innately resistant glioblastoma cells mediate their sustained survival and recurrence.

Abstract: Understanding of molecular events underlying resistance and relapse in glioblastoma (GBM) is hampered due to lack of accessibility to resistant cells from patients undergone therapy. Therefore, we mimicked clinical scenario in an in vitro cellular model developed from five GBM grade IV primary patient samples and two cell lines. We show that upon exposure to lethal dose of radiation, a subpopulation of GBM cells, innately resistant to radiation, survive and transiently arrest in G2/M phase via inhibitory pCdk1(Y15). Although arrested, these cells show multinucleated and giant cell phenotype (MNGC). Significantly, we demonstrate that these MNGCs are not pre-existing giant cells from parent population but formed via radiation-induced homotypic cell fusions among resistant cells. Furthermore, cell fusions induce senescence, high expression of senescence-associated secretory proteins (SASPs) and activation of pro-survival signals (pAKT, BIRC3 and Bcl-xL) in MNGCs. Importantly, following transient non-proliferation, MNGCs escape senescence and despite having multiple spindle poles during mitosis, they overcome mitotic catastrophe to undergo normal cytokinesis forming mononucleated relapse population. This is the first report showing radiation-induced homotypic cell fusions as novel non-genetic mechanism in radiation-resistant cells to sustain survival. These data also underscore the importance of non-proliferative phase in resistant glioma cells. Accordingly, we show that pushing resistant cells into premature mitosis by Wee1 kinase inhibitor prevents pCdk1(Y15)-mediated cell cycle arrest and relapse. Taken together, our data provide novel molecular insights into a multistep process of radiation survival and relapse in GBM that can be exploited for therapeutic interventions.