Abstract
Anoikis is a form of apoptosis induced when a cell loses contact with the extracellular matrix (ECM). Anoikis resistance is essential for metastasis formation, yet only detectable by in vitro experiments. We present a method for quantitation of putative anoikis-resistant (AR) subpopulations in colorectal carcinoma (CRC) and evaluate their prognostic significance. We studied 137 CRC cases and identified cell subpopulations with and without stromal or extracellular matrix (ECM) contact with hematoxylin-and-eosin-stained sections and immunohistochemistry for laminin and type IV collagen. Suprabasal cells of micropapillary structures and inner cells of cribriform and solid structures lacked both stromal contact and contact with ECM proteins. Apoptosis rate (M30) was lower in these subpopulations than in the other carcinoma cells, consistent with putative AR subpopulation. We determined the areal density of these subpopulations (number/mm2 tumor tissue), and their high areal density independently indicates low cancer-specific survival. In conclusion, we show evidence that subpopulations of carcinoma cells in micropapillary, cribriform, and solid structures are resistant to anoikis as shown by lack of ECM contact and low apoptosis rate. Abundance of these subpopulations is a new independent indicator of poor prognosis in CRC, consistent with the importance of anoikis resistance in the formation of metastasis.
Highlights
Anoikis is a form of apoptosis induced when a cell loses contact with the extracellular matrix (ECM)
We show here that subrabasal cells in micropapillary structures (MIPs) [11] and the inner cells in cribriform and solid structures are devoid of contact with mesenchymal areas or basement membrane proteins, and yet show a decreased apoptosis rate compared to tumor cells that are in contact with mesenchymal areas or basement membrane proteins at the stromal-epithelial interface of the tumors
These findings suggest that these subpopulations, all comprised of inner cells of multicellular carcinoma cell groups, represent tumor cells with anoikis resistance in CRC
Summary
Anoikis is a form of apoptosis induced when a cell loses contact with the extracellular matrix (ECM). We present a method for quantitation of putative anoikis-resistant (AR) subpopulations in colorectal carcinoma (CRC) and evaluate their prognostic significance. We show evidence that subpopulations of carcinoma cells in micropapillary, cribriform, and solid structures are resistant to anoikis as shown by lack of ECM contact and low apoptosis rate. Abundance of these subpopulations is a new independent indicator of poor prognosis in CRC, consistent with the importance of anoikis resistance in the formation of metastasis. We have shown that in carcinomas, anoikis resistance allows cells to form multicellular clusters where the inner cells lose their contact with the
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