Tumor Autocrine Motility Factor Is an Angiogenic Factor That Stimulates Endothelial Cell Motility

Department of Hygienics, Gifu Pharmaceutical University, Gifu, 502, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 08/2001; 285(1):118-28. DOI: 10.1006/bbrc.2001.5135
Source: PubMed


Autocrine motility factor (AMF) is a type of tumor-secreted cytokine which primarily stimulates tumor cell motility via receptor-mediated signaling pathways, and is thought to be connected to tumor progression and metastasis. Using in vivo models, we showed that critical neovascularization responded to a biological amount of AMF. This angiogenic activity was fixed by specific inhibitors against AMF. AMF stimulated in vitro motility of human umbilical vein endothelial cells (HUVECs), inducing the expression of cell surface AMF receptor localizing a single predominant perinuclear pattern closely correlated with its motile ability. AMF also elicited the formation of tube-like structures mimicking angiogenesis when HUVECs were grown in three-dimensional type I collagen gels. We further immunohistochemically detected AMF receptors on the surrounding sites of newborn microvessels. These findings suggest that AMF is a possible tumor progressive angiogenic factor which may act in a paracrine manner for the endothelial cells in the clinical neoplasm, and it will be a new target for antiangiogenic treatment.

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    • "3.1. MMP3 expression and kinase phosphorylation were enhanced in the AMF-high expression tumor cell line Two stable transfectant cell clones were isolated [5] [6] [7] [8], HT- 1080/vector as a mock cell line and HT-1080/AMF as a human AMF-high expression line, which had the pBK-CMV expression vector only and pBK-CMV-human AMF, respectively. As shown in Fig. 1, the HT-1080 parent line and HT-1080/vec- tor line were very similar, but the over-expression of AMF was manifested by its increased mRNA level (Fig. 1A) and cellular protein (Fig. 1C) in the HT-1080/AMF line. "
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    ABSTRACT: The autocrine motility factor (AMF) is a multifunctional protein that is involved in tumor progression including enhanced invasiveness via induction of matrix metalloproteinase-3 (MMP3). The increase in MMP3 was found in an AMF-high production tumor cell line, and c-Jun, c-Fos and mitogen-activated protein kinases (MAPKs) were also highly phosphorylated compared with the parent line. AMF stimulation induced the rapid phosphorylation of the cellular MAPK cascade and MMP3 secretion, which was blocked using a specific MAPK inhibitor. Results of this study suggest that AMF stimulation stimulates MMP3 expression via a MAPK signaling pathway.
    Full-text · Article · Jul 2008 · FEBS Letters
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    • "AMF/PGI exhibits anti-apoptotic activity by downregulating Apaf-1 and caspase-9 expression [26]. AMF/PGI is also an angiogenic factor, whose expression is induced under hypoxic conditions in response to expression of HIF-1, and crosstalk between AMF/PGI and VEGF regulates both induction of AMF/PGI and AMF/PGI promotion of angiogenesis [27]–[29]. AMF/PGI overexpression induces cellular transformation and promotes tumorigenicity as well as the formation of larger tumors and metastases upon orthotopic implantation of PaCa-2 pancreatic tumor cells, while partial AMF/PGI knockdown induces cellular senescence [22], [30], [31]. Increased AMF/PGI levels in the urine and serum of cancer patients is associated with the presence of colorectal, breast, lung, kidney and gastrointestinal carcinomas [32]–[37]. "
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    ABSTRACT: Autocrine motility factor/phosphoglucose isomerase (AMF/PGI) is the extracellular ligand for the gp78/AMFR receptor overexpressed in a variety of human cancers. We showed previously that raft-dependent internalization of AMF/PGI is elevated in metastatic MDA-435 cells, but not metastatic, caveolin-1-expressing MDA-231 cells, relative to non-metastatic MCF7 and dysplastic MCF10A cells suggesting that it might represent a tumor cell-specific endocytic pathway. Similarly, using flow cytometry, we demonstrate that raft-dependent endocytosis of AMF/PGI is increased in metastatic HT29 cancer cells expressing low levels of caveolin-1 relative to metastatic, caveolin-1-expressing, HCT116 colon cells and non-metastatic Caco-2 cells. Therefore, we exploited the raft-dependent internalization of AMF/PGI as a potential tumor-cell specific targeting mechanism. We synthesized an AMF/PGI-paclitaxel conjugate and found it to be as efficient as free paclitaxel in inducing cytotoxicity and apoptosis in tumor cells that readily internalize AMF/PGI compared to tumor cells that poorly internalize AMF/PGI. Murine K1735-M1 and B16-F1 melanoma cells internalize FITC-conjugated AMF/PGI and are acutely sensitive to AMF/PGI-paclitaxel mediated cytotoxicity in vitro. Moreover, following in vivo intratumoral injection, FITC-conjugated AMF/PGI is internalized in K1735-M1 tumors. Intratumoral injection of AMF/PGI-paclitaxel induced significantly higher tumor regression compared to free paclitaxel, even in B16-F1 cells, known to be resistant to taxol treatment. Treatment with AMF/PGI-paclitaxel significantly prolonged the median survival time of tumor bearing mice. Free AMF/PGI exhibited a pro-survival role, reducing the cytotoxic effect of both AMF/PGI-paclitaxel and free paclitaxel suggesting that AMF/PGI-paclitaxel targets a pathway associated with resistance to chemotherapeutic agents. AMF/PGI-FITC uptake by normal murine spleen and thymus cells was negligible both in vitro and following intravenous injection in vivo where AMF/PGI-FITC was selectively internalized by subcutaneous B16-F1 tumor cells. The raft-dependent endocytosis of AMF/PGI may therefore represent a tumor cell specific endocytic pathway of potential value for drug delivery to tumor cells.
    Full-text · Article · Feb 2008 · PLoS ONE
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    • "The ligand–receptor interaction on the cell surface is the initial step for AMF-stimulating cell motility signaling . Our previous study showed that normal human vascular endothelial cells express AMFR which was responsible for AMF motile stimulation [33]. If AMF secreted from ''Ehrlich þ'' cells may affect the host, it is expected that the peritoneal wall and diaphragm cells should express AMFR. "
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    ABSTRACT: Accumulation of ascites fluid often observed in some solid tumors is one of the most devastating conditions of a patient's difficulty in responding to treatment, and to a decrease in the quality of life. Various factors are thought to be associated with the formation of cancer-induced fluid accumulation and hyperpermeability of a blood vessel is thought to go with this process. Here, we report a new factor that is involved in this process, e.g., autocrine motility factor (AMF). AMF is a tumor-related cytokine which stimulates the tumor cell locomotion and migration and promotes tumor cell invasion during metastasis. AMF secretion and its receptor (AMFR) expression in tumor cells are closely correlated with disease aggravation of convalescence. The response of endothelial or mesothelial cellular morphological alternation to AMF leads to motile enhancement and vascular permeability. Tumor AMF induces gaps in an endothelial or mesothelial monolayer by stimulating a cellular movement, and accelerates the ascites accumulation. And treatment experiment with anti-AMF antibody succeeded in the reduction of the ascites accumulation, which renders AMF to the target molecule. It is suggested that AMF is one of the significant factors which relates to various pathological malignancies induced by tumor mass, and understanding of its function could benefit prognosis and treatment.
    Full-text · Article · May 2002 · Biochemical and Biophysical Research Communications
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