Cancer–stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis

Abstract

Interactions between cancer cells and stromal cells, including blood vessel endothelial cells (BECs), lymphatic vessel endothelial cells (LECs), bone marrow-derived angiogenic cells (BMDACs) and other bone marrow-derived cells (BMDCs) play important roles in cancer progression. Intratumoral hypoxia, which affects both cancer and stromal cells, is associated with a significantly increased risk of metastasis and mortality in many human cancers. Recent studies have begun to delineate the molecular mechanisms underlying the effect of intratumoral hypoxia on cancer progression. Reduced O2 availability induces the activity of hypoxia-inducible factors (HIFs), which activate the transcription of target genes encoding proteins that play important roles in many critical aspects of cancer biology. Included among these are secreted factors, including angiopoietin 2, angiopoietin-like 4, placental growth factor, platelet-derived growth factor B, stem cell factor (kit ligand), stromal-derived factor 1, and vascular endothelial growth factor. These factors are produced by hypoxic cancer cells and directly mediate functional interactions with BECs, LECs, BMDACs and other BMDCs that promote angiogenesis, lymphangiogenesis, and metastasis. In addition, lysyl oxidase (LOX) and LOX-like proteins, which are secreted by hypoxic breast cancer cells, remodel extracellular matrix in the lungs, which leads to BMDC recruitment and metastatic niche formation.

Lysyl oxidase activates cancer stromal cells and promotes gastric cancer progression: quantum dot-based identification of biomarkers in cancer stromal cells

“…49 In addition, LOX would lead to BMDC recruitment, which was the major source for infiltration of inflammation cells. 50,51 Morphological and quantitative analyses of this study indicated that the expression of LOX could promote the infiltration of macrophages, the ECM remodeling, the angiogenesis, the maturation of neo-microvessel, the secretion of MMP-9 and the degradation of type IV collagen (Table 2). Survival analysis indicated that those stromal parameters were independent risk factors for OS or DFS and would be considered as the marker for stromal activation (Table 4).…”

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase

“…The HIF transcription factor, which consists of a labile a subunit and a stable b subunit, is a master regulator of genes that promote adaptation to hypoxia, including genes linked to metabolism, angiogenesis, and proliferation (Semenza 2013). HIF provided the first example of the use of prolyl hydroxylation as an intracellular signal.…”

Contrôle de la croissance et de la dissémination tumorales par le microenvironnement

“…Le microenvironnement tumoral peut se définir comme l'ensemble des facteurs moléculaires, cellulaires et tissulaires capables d'influencer ou d'être influencés par les cellules tumorales [40] ( §). Au niveau tissulaire, la MEC, les vaisseaux sanguins et lymphatiques, ainsi que l'hypoxie, jouent des rôles importants dans le développement de tumeurs primaires et leur dissémination [6][7][8]. Au niveau cellulaire, trois catégories de protagonistes peuvent être distinguées en fonction de leur origine et de leurs fonctions [2] : les cellules vasculaires angiogéniques -cellules endothéliales et péricytes ; les cellules fibroblastiques associées aux cancers, comprenant les fibroblastes (CAF pour cancer associated fibroblasts) [41] ( §), mais aussi les adipocytes ou des cellules mésenchymateuses moins diffé-renciées [42] …”

“…L'accumulation de VEGF dans les tumeurs, qui résulte en partie de l'hypoxie (le gène codant pour le VEGF est un gène cible du facteur de transcription HIF-1 induit par l'hypoxie) [8] conduit à la perte progressive des tight junctions (jonctions serrées) des cellules angiogéniques, et à une diminution du nombre de péricytes. Ceci crée une perméabilisation des vaisseaux, facilitant l'intravasation (passage dans le sang) des cellules tumorales [29].…”