Thrombospondin 2 inhibits metastasis of human malignant melanoma through microenvironment-modification in NOD/SCID/γc null (NOG) mice

Tsuyoshi Chijiwa, Yoshiyuki Abe, Norihiro Ikoma, Hitoshi Yamazaki, Hideo Tsukamoto, Hiroshi Suemizu, Kenji Kawai, Masatoshi Wakui, Chiyoko Nishime, Hozumi Matsumoto, Masahiro Matsuyama, Masaya Mukai, Yoshito Ueyama, Masato Nakamura

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18 Citations (Scopus)

Abstract

Thrombospondin (TSP) 2 interacts with matrix metalloproteinases (MMPs) and matrix serine proteases such as plasminogen activator (PA). Malignant melanoma is an aggressive human neoplasm showing aggressive metastatic features. We examined the effects of TSP2 gene introduction in the human malignant melanoma cell line A375. We established three clones transfected with human TSP2 (A375/TSP2). The in vitro invasiveness was remarkably suppressed (42-61%) in the TSP2-transfectants, while growth properties were preserved. The A375/ TSP2 showed significantly decreased liver metastatic potential (liver weight: 3.88±0.30 g in A375/TSP2, 7.07±0.67 g in vector-transfectant (A375/V), p<0.01, Mann-Whitney U test) in super immuno-deficient mice (NOD/SCID/SCID/γcnull, NOG). The PA inhibitor-1 (PAI-1) and PAI-2 mRNAs were significantly overexpressed in A375/TSP2. The increased activities of PAI-1 and PAI-2 were confirmed by reverse zymography. The vascularity of metastatic lesions was significantly decreased in A375/TSP2 (vascular density: 0.62±0.15% in A375/TSP2, 4.96±0.61% in A375/V, p<0.01, Welch test). These results suggest that TSP2 suppresses hematogenous metastasis through micro-environment- modification including PAI up-regulation and anti-vascularization in human malignant melanoma.

Original languageEnglish
Pages (from-to)5-13
Number of pages9
JournalInternational journal of oncology
Volume34
Issue number1
DOIs
Publication statusPublished - 2009 Apr 20
Externally publishedYes

Keywords

  • Malignant melanoma
  • Metastasis
  • Microenvironment
  • Mouse model
  • Plasminogen activator
  • Thrombospondin 2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chijiwa, T., Abe, Y., Ikoma, N., Yamazaki, H., Tsukamoto, H., Suemizu, H., Kawai, K., Wakui, M., Nishime, C., Matsumoto, H., Matsuyama, M., Mukai, M., Ueyama, Y., & Nakamura, M. (2009). Thrombospondin 2 inhibits metastasis of human malignant melanoma through microenvironment-modification in NOD/SCID/γc null (NOG) mice. International journal of oncology, 34(1), 5-13. https://doi.org/10.3892/ijo_00000123