Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-β-disrupted diffuse-type gastric carcinoma.

• Diffuse-type gastric carcinoma is characterized by rapid progression and poor prognosis. High expression of transforming growth factor (TGF)-β and thick stromal fibrosis are observed in this type of gastric carcinoma. We have previously shown that disruption of TGF-β signaling via introduction of a dominant negative form of the TGF-β type II receptor (dnTβRII) into diffuse-type gastric cancer cell lines, including OCUM-2MLN, caused accelerated tumor growth through induction of tumor angiogenesis in vivo. In the present study, we show that TGF-β induces upregulation of expression of tissue inhibitor of metalloproteinase 2 (TIMP2) in the OCUM-2MLN cell line in vitro, and that expression of TIMP2 is repressed by dnTβRII expression in vivo. Transplantation of the OCUM-2MLN cells to nude mice exhibited accelerated tumor growth in response to dnTβRII expression, which was completely abolished when TIMP2 was coexpressed with dnTβRII. Although the blood vessel density of TIMP2-expressing tumors was only slightly decreased, the degree of hypoxia in tumor tissues was significantly increased and pericytes covering tumor vasculature were decreased by TIMP2 expression in OCUM-2MLN cells, suggesting that the function of tumor vasculatures was repressed by TIMP2 and consequently tumor growth was reduced. These findings provide evidence that one of the mechanisms of the increase in angiogenesis in diffuse-type gastric carcinoma is the downregulation of the anti-angiogenic protein TIMP2.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Animals

Anoxia

Cell Line

Tumor

Cell Proliferation

drug effects

Gene Expression Regulation

Neoplastic

drug effects

Humans

Immunoblotting

Immunohistochemistry

Male

Mice

Mice

Inbred BALB C

Mice

Nude

Neoplasms

Experimental

genetics

metabolism

pathology

Neovascularization

Pathologic

genetics

metabolism

pathology

Protein-Serine-Threonine Kinases

genetics

metabolism

Receptors

Transforming Growth Factor beta

genetics

metabolism

Reverse Transcriptase Polymerase Chain Reaction

Signal Transduction

drug effects

Stomach Neoplasms

genetics

metabolism

pathology

Tissue Inhibitor of Metalloproteinase-2

genetics

metabolism

Transforming Growth Factor beta

metabolism

pharmacology

Transplantation

Heterologous

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