RETRACTED ARTICLE: HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs

Abstract

Most cases of breast cancer mortality are due to vascular metastasis. Breast cancer cells must intravasate through endothelial cells (ECs) to enter a blood vessel in the primary tumor and then adhere to ECs and extravasate at the metastatic site. In this study we demonstrate that inhibition of hypoxia-inducible factor activity (HIF) in breast cancer cells by RNA interference or digoxin treatment inhibits primary tumor growth and also inhibits the metastasis of breast cancer cells to the lungs by blocking the expression of angiopoietin-like 4 (ANGPTL4) and L1 cell adhesion molecule (L1CAM). ANGPTL4 is a secreted factor that inhibits EC-EC interaction, whereas L1CAM increases the adherence of breast cancer cells to ECs. Interference with HIF, ANGPTL4, or L1CAM expression inhibits vascular metastasis of breast cancer cells to the lungs.

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

“…A large and rapidly growing body of experimental data indicates that in hypoxic breast cancer cells, HIFs function as master regulators by mediating the expression of a large battery of genes that promote multiple steps in the metastatic process (52). Treatment of SCID mice bearing orthotopic transplants of human breast cancer cells with drugs that inhibit HIF activity results in a dramatic reduction of primary tumor growth, local metastasis to axillary lymph nodes, and distant metastasis to the lungs (28,29,53,54). These preclinical data provide a scientific foundation for clinical trials that test the safety and efficacy of adding HIF inhibitors to current chemotherapy regimens.…”

“…3B). For comparison, expression of L1CAM, which is another known HIF target gene expressed in breast cancer (28), was significantly correlated with only three of the four reference genes. RAB22A mRNA levels in primary breast cancers that were greater than the mean were associated with significantly decreased overall survival (P = 0.0004; n = 737 patients) and distant metastasis-free survival (P = 0.0195; n = 1,379 patients) in 10-y Kaplan-Meier analyses (Fig.…”

“…In breast cancer, overexpression of HIF-1α or HIF-2α is associated with metastasis, treatment failure, and patient mortality (21)(22)(23)(24)(25)(26). HIFs are required for lymph node and lung metastasis in both autochthonous (27) and orthotopic (28)(29)(30) mouse models of breast cancer and activate the transcription of genes encoding proteins that are required for multiple steps in the invasion and metastasis of breast cancer cells (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38).…”

Vaisseaux sanguins et tumeurs ou l’art du dialogue

“…Les effets tumoraux de ce dernier sont nombreux, notamment au cours de la transition épithélio-mésen-chymateuse et de l'évasion immune [13]. Le TGF- intervient également dans l'angiogenèse tumorale en induisant l'expression de HIF-1 (hypoxia inducible factor-1a) et, donc, du VEGF [14]. Dans les carcinomes mammaires métastatiques, le TGF- augmente l'expression de la protéine angiopoïétine-like 4, qui dissocie les jonctions endothéliales, ce qui permet l'infiltration vaisseaux sanguins et l'inhibition de la croissance tumorale dans de nombreux modèles expérimentaux de xénogreffes.…”

“…L'exposition des cellules endothéliales au VEGF déclenche une cascade de signalisation qui culmine en l'internalisation de la VE-cadhérine et le démantèlement des jonctions cellulaires, résultant en une perméabilité accrue [11]. De plus, la surexpression du VEGF est associée à la réduction de l'infiltration des cellules T et à des cellules tumorales dans les poumons [14]. Les cellules tumorales sécrètent aussi des chimiokines.…”