BMP9, but not BMP10, acts as a quiescence factor on tumor growth, vessel normalization and metastasis in a mouse model of breast cancer

Abstract

BackgroundAngiogenesis has become an attractive target for cancer therapy. However, despite the initial success of anti-VEGF (Vascular endothelial growth factor) therapies, the overall survival appears only modestly improved and resistance to therapy often develops. Other anti-angiogenic targets are thus urgently needed. The predominant expression of the type I BMP (bone morphogenetic protein) receptor ALK1 (activin receptor-like kinase 1) in endothelial cells makes it an attractive target, and phase I/II trials are currently being conducted. ALK1 binds with strong affinity to two ligands that belong to the TGF-ß family, BMP9 and BMP10. In the present work, we addressed their specific roles in tumor angiogenesis, cancer development and metastasis in a mammary cancer model.MethodsFor this, we used knockout (KO) mice for BMP9 (constitutive Gdf2-deficient), for BMP10 (inducible Bmp10-deficient) and double KO mice (Gdf2 and Bmp10) in a syngeneic immunocompetent orthotopic mouse model of spontaneous metastatic breast cancer (E0771).ResultsOur studies demonstrate a specific role for BMP9 in the E0771 mammary carcinoma model. Gdf2 deletion increased tumor growth while inhibiting vessel maturation and tumor perfusion. Gdf2 deletion also increased the number and the mean size of lung metastases. On the other hand, Bmp10 deletion did not significantly affect the E0771 mammary model and the double deletion (Gdf2 and Bmp10) did not lead to a stronger phenotype than the single Gdf2 deletion.ConclusionsAltogether, our data show that in a tumor environment BMP9 and BMP10 play different roles and thus blocking their shared receptor ALK1 is maybe not appropriate. Indeed, BMP9, but not BMP10, acts as a quiescence factor on tumor growth, lung metastasis and vessel normalization. Our results also support that activating rather than blocking the BMP9 pathway could be a new strategy for tumor vessel normalization in order to treat breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0885-1) contains supplementary material, which is available to authorized users.

The Interactivity between TGFβ and BMP Signaling in Organogenesis, Fibrosis, and Cancer

“…BMP9 was found to stimulate the proliferation of ovarian cancer cells, whereas it induces apoptosis in prostate cancer cells [129,130,131,132,133,134,135]. In an immunocompetent syngeneic orthotopic spontaneous mouse model of breast cancer (E0771) BMP9, but not BMP10, was shown to exert a protective action against tumor growth and lungs dissemination, probably via inducing quiescence in cancer cells [136]. However, the induction of cancer cells dormancy may turn into a double-edged weapon as it only represents a temporarily suspended malignant progression that may desensitize these cells to chemotherapy [137].…”

EO771, is it a well‐characterized cell line for mouse mammary cancer model? Limit and uncertainty

“…Indeed, the advantage of having a tumor line from the most used mouse strain, C57BL/6, makes it possible to have a lot of genetically modified models of this strain. Thus, EO771 cell tumor growth can be evaluated i) in KO mice for E2 (estradiol), 23 apolipoprotein E and aromatase, 42 IFN‐γ receptor, 48 natural killer lytic‐associated molecule (NKLAM), 33 MMP13, 49 calcium‐independent phospholipase A2 β, 50 IGFBP‐3, 21,51,52 DUSP1, 53 GDF2, 54 BMP10, 54 and mKIAA1462 55 but also ii) in transgenic models such as mice overexpressing IL‐15, 56 obese, 13,35 NKC KD (exhibiting silenced Ly49 expression in NK cells), 46 GFP‐LC3 (LC3 linked to GFP expressing mice), 57 mice transgenically modified to express the HER2 proto‐oncogene (ERBB2) 58 or FAT‐1 (gene leading to the endogenous formation of ω3‐Polyunsaturated fatty acid from ω6‐Polyunsaturated fatty acid) 44,59 …”

Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation

“…Up until now, this hypothesized tumor-starving mechanism has not been clinically verified. Another hypothesis involves the remodeling of the remaining abnormal vessels [4, 5], also known as “vessel normalization”. In the latter hypothesis, the drugs not only suppress both the growth and metastasis of the tumor but also enhance the chemosensitization of cancer cells by improving the vascular maturity and functionality, and ameliorating tumor hypoxia [6].…”