MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis.

By Sachie Hiratsuka, K. Nakamura, Shinobu Iwai, M. Murakami, T. Itoh, H. Kijima, J. Shipley, R. Senior, M. Shibuya. Cancer Cell, 2002

906 citations recorded by the source corpus.

The molecular mechanism of tissue-specific metastasis in tumors endogenously expressing members of the vascular endothelial growth factor (VEGF) family is not yet clear. Here we demonstrate that MMP9 is specifically induced in premetastatic lung endothelial cells and macrophages by distant primary tumors via VEGFR-1/Flt-1 tyrosine kinase (TK) and that it significantly promotes lung metastasis. In a genetic approach using mice, suppression of MMP9 induction by deletion of either VEGFR-1TK or MMP9 markedly reduced lung metastasis. Furthermore, the MMP9 levels in endothelial cells of normal lung lobes from patients carrying distant tumors were significantly elevated as compared with those from patients without tumors. Thus, a block of MMP9 induction via VEGFR-1 inhibition could be useful for the prevention of tumor metastasis in lung.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bcd6712a844fa877fc2ee2d74f7fbe0424cfd6e4

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Citations in the corpus

Glioma cancer stem cells induce immunosuppressive macrophages/microglia. (2010, background): “Tumor-associated M2 MFs have been shown to promote cancer by secreting proangiogenic factors and enhancing invasion(10,17) mediated by the production of soluble factors such as transforming growth factor-b (TGF-b),(18) interleukin (IL)-1,(19) vascular endothelial growth factor, and matrix metallopep”
Microenvironmental regulation of metastasis (2009, background): “Several other molecules have been identified as important in the creation of the niche, including the chemoattractants S100A8 and S100A9, and the metalloproteinase MMP9, which liberates VEGFA locally and promotes myeloid cell recruitment through VEGFR1 signallin”
Tumor‐associated macrophages (TAM) as major players of the cancer‐related inflammation (2009, background): “Other evidence comes from the influence of lung macrophages on endothelial cells, which leads to MMP-9 secretion via a VEGFR-1-dependent mechanism [107].”
Preparing the "soil": the premetastatic niche. (2006, background): “(12) have shown alterations in MMPs with the up-regulation of MMP-9 preceding tumor metastasis to the lung.”
The Yin‐Yang of tumor‐associated macrophages in neoplastic progression and immune surveillance (2008, background): “A model by which macrophages promote tumor invasion and metastasis includes expression of their proteolytic activity and subsequent breakdown of the basement membrane around the pre-invasive tumors, thereby enhancing the ability of tumor cells to escape into the surrounding stroma (33).”
Tumour-educated macrophages promote tumour progression and metastasis (2004, background): “In these experiments, the ability of the injected cells to colonize and grow in the host lungs only occurred in mice that also carried a separate primary tumou”
Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. (2013, methodology): “Using the flt-1 TK-/- mice, our study as well as recent studies by others have shown that VEGFR-1 signaling is important for tumor growth, metastasis, and chronic arthritis in mice (27-31).”
Extracellular matrix: a dynamic niche component during cancer progression (2012, neutral): “Once there, VEGFR1+ hematopoietic pro genitor cells secrete MMP9, which is known to play a role in lungspecific metastasis (Hiratsuka et al., 2002), and thus fur ther modulate and deregulate the premetastatic niche.”
Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. (2007, background): “Whether aPlGF also blocks the role of macrophages in establishing the premetastatic niche, as suggested by genetic data using VEGFR-1/TK / mice (Hiratsuka et al., 2002), remains to be established.”