Aggregation formation mediated anoikis resistance of BEL7402 hepatoma cells.
Zhiyong ZhangLihui HanLili CaoXiaohong LiangYugang LiuHua LiuJuan DuZhonghua QuChangjun ZhuSuxia LiuHui LiWensheng Sun
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Abstract:
Anoikis resistance is the prerequisite of cancer cells metastasis. Elucidation of the mechanism of anoikis resistance remains a significant challenge. We reported here a model to mimic anoikis resistant process of hepatoma cells in vitro. Experimental results indicated cell to cell aggregation could mediate anoikis resistance of BEL7402 hepatoma cells. Further investigation of these aggregations indicated the biological properties changed greatly after the hepatoma cells lost their anchorage. Aggregation forming process could be separated into three distinct phases according to their biological characteristics, comprising of premature phase, mature phase and postmature phase. Mature phase aggregations have the premium state of cell viability and may mimic the metastatic cells in the circulating system. Biological properties of these three phases aggregations were studied in details including morphological alteration, cell viability and microarray expression profiles. It indicated there was a great upregulation of adhesion molecules during the process of aggregation formation and the cell to cell contact in the aggregation may be mediated independent of calcium involved adhesion pathway. This model might shed light on the anoikis resistance mechanism of hepatoma cells and help to develop new therapies that may target the anoikis resistant hepatoma cells in the metastasis process.Keywords:
Anoikis
Viability assay
Anoikis is a programmed cell death occurring upon cell detachment from the correct extracellular matrix, thus disrupting integrin ligation. It is a critical mechanism in preventing dysplastic cell growth or attachment to an inappropriate matrix. Anoikis prevents detached epithelial cells from colonizing elsewhere and is thus essential for tissue homeostasis and development. As anchorage-independent growth and epithelial-mesenchymal transition, two features associated with anoikis resistance, are crucial steps during tumour progression and metastatic spreading of cancer cells, anoikis deregulation has now evoked particular attention from the scientific community. The aim of this review is to analyse the molecular mechanisms governing both anoikis and anoikis resistance, focusing on their regulation in physiological processes, as well as in several diseases, including metastatic cancers, cardiovascular diseases and diabetes.
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Anoikis, a specific form of programmed cell death, is triggered by cell detachment from extracellular matrix or adjacent cell. Studies have found that the most kinds of tumor cells had anoikis resistance characteristic, which may inhibit pro-apoptosis protein, block anoikis inside and outside pathways, up-regulate pro-survival factor signals, and promote survival, invasion and metastasis of tumor cells in the end. The review summarized the mechanism of anoikis and the relationship between anoikis and tumor invasion and the metastasis.
Key words:
Neoplasms; Anoikis; Neoplasm invasiveness; Neoplasm metastasis
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Detachment from the extracellular matrix induces a form of programmed cell death termed anoikis. Resistance to anoikis permits cancer cells to survive in systemic circulation and facilitates their metastasis to distant organs. It is well known that S100A4 is overexpressed in many tumors and involved in tumor metastasis, but the mechanisms of the metastasis-promoting function of S100A4 are not fully understood. We hypothesized that S100A4 might play a role in anoikis of gastric cancer cells and further affects their metastasis. To test this hypothesis, we changed the expression of S100A4 by means of RNA interference or experimental overexpression and investigated the effect on anoikis. We found that knockdown of S100A4 by RNA interference led to significantly increased anoikis, whereas overexpression of S100A4 resulted in inhibition of anoikis. Furthermore, we provide evidence that inhibition of S100A4 resulted in the downregulation of α5 and αv integrin expression. These findings suggest that S100A4 protects gastric cancer cells from anoikis by regulation of αv and α5 integrin expression, which sheds a novel light for the role of S100A4 in cancer metastasis.
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Anoikis is a form of apoptosis induced by detachment of adherent cells from the extracellular matrix or inappropriate cell-matrix interactions.Resistance to anoikis is a hallmark of metastatic cancer cells which leads to cancer cells evading anoikis and thereby survives after detachment from their primary site,and metastasizing to distant organs.Both death receptor-mediated extrinsic pathway and mitochondrial-mediated intrinsic pathway contribute to anoikis.Phosphatidylinositol 3-kinase(PI3K)/Akt signal pathway and mitogen-activated protein kinase(MAPK) signal are major regulator of anoikis.In addition,oncogene TrkB and tumor suppressor gene PTEN may also contribute to anoikis regulation.Some studies suggested some anti-cancer Chinese herbs or components may inhibit anchoring-independent cancer cell growth and induces anoikis.
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Inhibitory Effects of Alendronate on Adhesion and Viability of Preosteoblast Cells on Titanium Discs
Abstract Objective This study aimed to investigate the effects of alendronate (ALN; a bisphosphonate) on adhesion and viability of preosteoblasts using different cell passages on sandblasted and acid-etched (SLA) Ti surfaces. Materials and Methods Preosteoblast, MC3T3, cells (passage 42; P42 and passage 62; P62) were cultured with ALN (1 and 5 µM) on cell culture plate for 7 days. Cells were lifted, counted, and seeded on SLA Ti surfaces. Cells were incubated on the discs for 6 hours to examine cell adhesion by using confocal microscopy and for 24 hours to determine cell viability by using MTT assay. Results ALN interfered with cell adhesion on Ti surfaces by reducing the cell number in both cell passages. Nuclei of untreated cells showed oval shape, whereas some nuclei of ALN-treated cells demonstrated crescent and condensed appearance. ALN at 1 and 5 µM significantly decreased nuclear area and perimeter in P42, while ALN at 5 µM reduced nuclear area and perimeter in P62. After 24 hours, cells (P42) grown on Ti surfaces showed decreased cell viability when culturing with 5 µM ALN. Conclusion ALN reduced cell adhesion and viability of preosteoblasts on Ti surfaces. ALN treatment seemed to exert higher inhibitory effects on nuclear shape and size as well as cell viability in lower cell passage. This led to the reduction in cell to implant surface interaction after encountering bisphosphonate treatment.
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Normal epithelial and endothelial cells require attachment to extracellular matrix (ECM) proteins to grow or survive. In these anchorage -dependent cells, loss of interaction with the ECM proteins triggers apoptosis whichis termed anoikis. Anoikis undoubtedly plays an essential role in the development and organization of normal tissues through its inhibitory effect on unfavorable cellular proliferation at inappropriate locations. In this regard, anoikis contributes to the maintenance of the physiological state. Importantly, disturbance of anoikis may allow cell proliferation at inappropriate sites and thus may be tightly linked to cancer development. Indeed, we have found that suppression of anoikis promotes peritoneal dissemination or metastasis of several carcinoma cells. These data imply that clarification of the molecular mechanism which regulates anoikis will, in turn, greatly help the regulation of cancer progression. Here we summarize recent advances in the field of anoikis regulation.
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Anoikis (or cell-detachment-induced apoptosis) is a self-defense strategy that organisms use to eliminate 'misplaced' cells, i.e. cells that are in an inappropriate location. Occasionally, detached or misplaced cells can overcome anoikis and survive for a certain period of time in the absence of the correct signals from the extracellular matrix (ECM). If cells are able to adapt to their new environment, then they have probably become anchorage-independent, which is one of the hallmarks of cancer cells. Anoikis resistance and anchorage-independency allow tumor cells to expand and invade adjacent tissues, and to disseminate through the body, giving rise to metastasis. Thus, overcoming anoikis is a crucial step in a series of changes that a tumor cell undergoes during malignant transformation. Tumor cells have developed a variety of strategies to bypass or overcome anoikis. Some strategies consist of adaptive cellular changes that allow the cells to behave as they would in the correct environment, so that induction of anoikis is aborted. Other strategies aim to counteract the negative effects of anoikis induction by hyperactivating survival and proliferative cascades. The recently discovered processes of autophagy and entosis also highlight the contribution of these mechanisms to rendering the cells in a dormant state until they receive a signal initiated at the ECM, thereby circumventing anoikis. In all situations, the final outcome is the ability of the tumor to grow and metastasize. A better understanding of the mechanisms underlying anoikis resistance could help to counteract tumor progression and prevent metastasis formation.
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