Journal
ONCOTARGET
Volume 5, Issue 21, Pages 10529-10545Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2470
Keywords
Tumor angiogenesis; angiogenic switch; extracellular matrix; matrisome
Categories
Funding
- Institut National du Cancer (INCa)
- Association pour la Recherche sur le Cancer (ARC)
- Oncosuisse
- Agence Nationale de la Recherche (ANR)
- Ligue Regionale Grand-Est Contre le Cancer
- Fondation des Treilles
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Angiogenesis represents a rate-limiting step during tumor progression. Targeting angiogenesis is already applied in cancer treatment, yet limits of anti-angiogenic therapies have emerged, notably because tumors adapt and recur after treatment. Therefore, there is a strong need to better understand the molecular and cellular mechanisms underlying tumor angiogenesis. Using the RIP1-Tag2 transgenic murine model, we identified 298 genes that are deregulated during the angiogenic switch, revealing an ingression/expansion of specific stromal cell types including endothelial cells and pericytes, but also macrophages and perivascular mesenchymal cells. Canonical TGF-beta signaling is up-regulated during the angiogenic switch, especially in tumor-associated macrophages and fibroblasts. The matrisome, comprising extracellular matrix (ECM) and ECM-associated molecules, is significantly enriched, which allowed us to define the AngioMatrix signature as the 110 matrisomal genes induced during the RIP1-Tag2 angiogenic switch. Several AngioMatrix molecules were validated at expression level. Ablation of tenascin-C, one of the most highly induced ECM molecules during the switch, resulted in reduced angiogenesis confirming its important role. In human glioma and colorectal samples, the AngioMatrix signature correlates with the expression of endothelial cell markers, is increased with tumor progression and finally correlates with poor prognosis demonstrating its diagnostic and therapeutic potential.
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