Cell growth

About: Cell growth is a research topic. Over the lifetime, 104237 publications have been published within this topic receiving 3751303 citations. The topic is also known as: GO:0016049 & cellular growth.

Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion

Abstract: Although cellular senescence is believed to have a tumor suppressor function, senescent cells have been shown to increase the potential for growth of adjacent cancer cells in animal models. Replicatively senescent human fibroblasts increase the growth of cotransplanted cancer cells in vivo, but the role of cells that have undergone damage-mediated stress-induced premature senescence (SIPS) has not been studied in mouse transplant models. Here, we show that human fibroblasts that have undergone SIPS by exposure to the DNA-damaging agent bleomycin increase the growth of cotransplanted cancer cells (MDA-MB-231) in immunodeficient mice. Xenografts containing SIPS fibroblasts (SIPSF) exhibited early tissue damage as evidenced by fluid accumulation (edema). Cancer cells adjacent to the fluid showed increased DNA synthesis. Fluid accumulation, increased xenograft size, and increased cell proliferation were all reduced by the matrix metalloproteinase (MMP) inhibitor GM6001. MMPs and other genes characteristic of inflammation/tissue injury were overexpressed in SIPSF. Inhibition of MMP activity did not affect SIPSF stimulation of cancer cell proliferation in culture. However, another overexpressed product (hepatocyte growth factor) did have a direct mitogenic action on cancer cells. Based on the present results, we propose that senescent cells may promote cancer growth both by a direct mitogenic effect and by an indirect effect via tissue damage. Senescent stromal cells may cause an MMP-mediated increase in permeability of adjacent capillaries, thereby exposing incipient cancer cells to increased levels of mitogens, cytokines, and other plasma products. This exposure may increase cancer cell proliferation and result in promotion of preneoplastic cells.

A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth

Abstract: Cell growth, an increase in mass and size, is a highly regulated cellular event. The Akt/mTOR (mammalian target of rapamycin) signalling pathway has a central role in the control of protein synthesis and thus the growth of cells, tissues and organisms. A striking example of a physiological context requiring rapid cell growth is tissue repair in response to injury. Here we show that keratin 17, an intermediate filament protein rapidly induced in wounded stratified epithelia, regulates cell growth through binding to the adaptor protein 14-3-3sigma. Mouse skin keratinocytes lacking keratin 17 (ref. 4) show depressed protein translation and are of smaller size, correlating with decreased Akt/mTOR signalling activity. Other signalling kinases have normal activity, pointing to the specificity of this defect. Two amino acid residues located in the amino-terminal head domain of keratin 17 are required for the serum-dependent relocalization of 14-3-3sigma from the nucleus to the cytoplasm, and for the concomitant stimulation of mTOR activity and cell growth. These findings reveal a new and unexpected role for the intermediate filament cytoskeleton in influencing cell growth and size by regulating protein synthesis.

Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation.

Abstract: Dysregulated activation of Ras or its downstream effectors such as mitogen-activated protein kinase kinase and ERK has been shown to play a critical role in tumorigenesis of many cancer types. However, in melanoma, activating mutations in Ras are rarely observed and are limited to N-Ras in UV-exposed cells. In this study, we identify constitutively activated ERK in almost all melanoma cell lines and in tumor tissues tested, which is in contrast to normal melanocytes and several early stage radial growth phase melanoma lines where ERK can be activated by serum or growth factors. Constitutive activation of ERK is preceded by phosphorylation of mitogen-activated protein kinase kinase and c-RAF. In all of the melanoma cell lines tested, Ras is constitutively activated without underlying mutations. On the contrary, activating mutations in the kinase domain of BRAF are present in the majority of the cell lines tested. Furthermore, ERK activation can be partially inhibited from the cell surface using inhibitors of fibroblast growth factor and hepatocyte growth factor but not interleukin 8 signaling pathways. These data suggest that melanoma growth, invasion, and metastasis are attributable to constitutively activated ERK apparently mediated by excessive growth factors through autocrine mechanisms and BRAF kinase activation.

Developmental mechanisms underlying pathology of arteries

Abstract: This review tries to provide a general, and very speculative, view of growth control mechanisms that may be common to the development of blood vessels and to pathological processes including cell proliferation. From a developmental point of view, vascular growth is most likely to include local autocrine or paracrine mechanisms that permit the two cells of the vessel wall to grow, organize into the characteristic tubular and layered structures of the vessel wall, and eventually achieve a return to quiescence. The "real" mechanisms controlling growth in vivo are difficult to ascertain from studies in culture. For example, a large list of angiogenesis molecules must be able to generate endothelial replication, but in culture many of these molecules are inhibitory for each endothelial replication. Similarly, in culture, we have a long list of smooth muscle mitogens, but none of these have as of yet been proven to control smooth muscle growth in vivo. Endothelial growth control has been attributed to the presence of membrane molecules able to inhibit endothelial replication and to the actions of soluble growth factors and their receptors. Unfortunately for the former hypothesis we still lack specific molecules with the properties of contact inhibition of replication. The data discussed here, however, suggest that modulation of expression or function of cell-cell adhesive molecules could be critical both to morphogenic changes and to mitogenesis by release of cells from cell-cell contact. Moreover, our data and data from other laboratories suggest that angiogenic factors, including the HBGFs and TGF-beta, may function in angiogenesis by altering cell-cell and cell-cell substrate interactions rather than via a primary effect on cell replication. This view of angiogenesis is consistent with the absence of a mitogenic effect of some angiogenic factors. Although endothelial cell replication is obviously necessary to angiogenesis, the lack of mitogenic effect of some factors suggests a need for a more general explanation of the actions of angiogenic factors. Endothelial injury may be interrelated with smooth muscle growth. The simplest possibility is that a failure of the endothelial cell barrier function, due either to denudation or an increase in adhesivity for leukocytes, would permit access of platelets or leukocytes to the vessel wall. These extrinsic cells, in turn, would stimulate smooth muscle cell replication by release of growth factors. The second possibility is that the endothelial cell may itself release growth factors into the vessel wall.(ABSTRACT TRUNCATED AT 400 WORDS)