The Dual Effect of the BMP9–ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement?

Ayuso-Íñigo, Blanca; Méndez-García, Lucía A.; Pericacho, Miguel; Muñoz‐Félix, José M.

doi:10.3390/cancers13215412

Cited by 11 publications

(7 citation statements)

References 169 publications

(239 reference statements)

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“…Although our previous studies demonstrate a role of ALK1 in regulating ECM production by ECM producing cells like fibroblasts, the biological role of ALK1 has been traditionally considered more relevant in the regulation of endothelial cell balance during development, cardiovascular diseases and tumor angiogenesis ( Ayuso-Inigo et al, 2021 ). To understand ALK1 function in tissue fibrosis is very important to consider two molecular players that regulate ALK1 activity: Its high affinity ligand BMP9 ( David et al, 2007b ) and the coreceptor endoglin ( Lebrin et al, 2004 ; López-Novoa and Bernabeu, 2010 ).…”

Section: Discussionmentioning

confidence: 87%

“…We observed lower vascular rarefaction in Alk1 +/− mice after 3 days of UUO. ALK1 regulates negatively the activation phase of angiogenesis ( Ayuso-Inigo et al, 2021 ) and it is expected that lower levels of ALK1 in Alk1 +/− mice lead to a maintained angiogenic phase or an impaired vessel regression phase, which also correlates with the higher VEGF levels observed in O kidneys from Alk1 +/− mice. Our observations are in concordance with those of Sharpfenecker et al (2011), who demonstrated in a kidney fibrosis model after irradiation that Alk1 +/− mice show lower vascular injury after 20 weeks of irradiation, and this correlated with higher levels of VEGF and VEGFR2 at that time point ( Scharpfenecker et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

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Endothelial Activin Receptor-Like Kinase 1 (ALK1) Regulates Myofibroblast Emergence and Peritubular Capillary Stability in the Early Stages of Kidney Fibrosis

Martı́nez-Salgado

Sánchez-Juanes²,

López-Hernández³

et al. 2022

Front. Pharmacol.

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Renal tubulo-interstitial fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) in the tubular interstitium during chronic kidney disease. The main source of ECM proteins are emerging and proliferating myofibroblasts. The sources of myofibroblasts in the renal tubular interstitium have been studied during decades, in which the epithelial contribution of the myofibroblast population through the epithelial-to-mesenchymal (EMT) process was assumed to be the major mechanism. However, it is now accepted that the EMT contribution is very limited and other mechanisms such as the proliferation of local resident fibroblasts or the transdifferentiation of endothelial cells seem to be more relevant. Activin receptor-like kinase 1 (ALK1) is a type I receptor which belongs to the transforming growth factor beta (TGF-β) superfamily, with a key role in tissue fibrosis and production of ECM by myofibroblast. Predominantly expressed in endothelial cells, ALK1 also plays an important role in angiogenesis and vessel maturation, but the relation of these processes with kidney fibrosis is not fully understood. We show that after 3 days of unilateral ureteral obstruction (UUO), ALK1 heterozygous mice (Alk1+/−) display lower levels of kidney fibrosis associated to a lower number of myofibroblasts. Moreover, Alk1+/− mice have a lower degree of vascular rarefaction, showing improved peritubular microvasculature after UUO. All these data suggest an important role of ALK1 in regulating vascular rarefaction and emergence of myofibroblasts.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Endothelial Activin Receptor-Like Kinase 1 (ALK1) Regulates Myofibroblast Emergence and Peritubular Capillary Stability in the Early Stages of Kidney Fibrosis

Martı́nez-Salgado

Sánchez-Juanes²,

López-Hernández³

et al. 2022

Front. Pharmacol.

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“…Recently, we reported that BMP9 is a crucial factor inducing the malignant nature of HCC and found that BMP9-ID1 signaling promotes cancer stem cell properties in EpCAM-positive HCC cells by activating Wnt/β-catenin signaling [9]. The role of BMP9 in angiogenesis is still controversial [14]; thus, we aimed to investigate the functional roles of BMP9 signaling in the activation of angiogenic signaling in HCC cells in the current study.…”

Section: Discussionmentioning

confidence: 98%

BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma

Chen

Nio

Tang

et al. 2022

IJMS

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Since hepatocellular carcinoma (HCC) is a typical hypervascular malignant tumor with poor prognosis, targeting angiogenesis is an important therapeutic strategy for advanced HCC. Involvement of bone morphologic protein 9 (BMP9), a transforming growth factor-beta superfamily member, has recently been reported in the development of liver diseases and angiogenesis. Here, we aimed to elucidate the role of BMP9 signaling in promoting HCC angiogenesis and to assess the antiangiogenic effect of BMP receptor inhibitors in HCC. By analyzing HCC tissue gene expression profiles, we found that BMP9 expression was significantly correlated with angiogenesis-associated genes, including HIF-1α and VEGFR2. In vitro, BMP9 induced HCC cell HIF-1α/VEGFA expression and VEGFA secretion. Silencing of the inhibitor of DNA-binding protein 1 (ID1), a transcription factor targeted by BMP9 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression and VEGFA secretion, resulting in decreased human umbilical vein endothelial cell (HUVEC) lumen formation. BMP receptor inhibitors, which inhibit BMP9-ID1 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression, VEGFA secretion, and HUVEC lumen formation. In vivo, the BMP receptor inhibitor LDN-212854 successfully inhibited HCC tumor growth and angiogenesis by inhibiting BMP9-ID1 signaling. In summary, BMP9-ID1 signaling promotes HCC angiogenesis by activating HIF-1α/VEGFA expression. Thus, targeting BMP9-ID1 signaling could be a pivotal therapeutic option for advanced HCC.

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“…What is exciting is that some active ingredients from TCM need to be relocated in angiogenic effects for the shared signaling pathways (such as MAPK and PI3K/Akt/mTOR), implying the viability of co-targeting angiogenesis and other phenotypes, including proliferation, apoptosis, and stem cell like-type. However, there are few studies to demonstrate the role of candidate molecules toward antiangiogenic factors or signalings, such as TNFα, TSP-1, TIMP, and TGF-β/BMP pathway ( Ayuso-Íñigo et al, 2021 ), but IL-8 seems to involve the crosstalk between angiogenesis and TME like VEGF ( Fousek et al, 2021 ). In clinical, these candidate drugs were more considered dietary supplements or adjuvants ( Table 3 ) for the anti-angiogenic strategy, beyond a single drug being used.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology

et al. 2022

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Tumor angiogenesis is one of the most important processes of cancer deterioration via nurturing an immunosuppressive tumor environment (TME). Targeting tumor angiogenesis has been widely accepted as a cancer intervention approach, which is also synergistically associated with immune therapy. However, drug resistance is the biggest challenge of anti-angiogenesis therapy, which affects the outcomes of anti-angiogeneic agents, and even combined with immunotherapy. Here, emerging targets and representative candidate molecules from ethnopharmacology (including traditional Chinese medicine, TCM) have been focused, and they have been proved to regulate tumor angiogenesis. Further investigations on derivatives and delivery systems of these molecules will provide a comprehensive landscape in preclinical studies. More importantly, the molecule library of ethnopharmacology meets the viability for targeting angiogenesis and TME simultaneously, which is attributed to the pleiotropy of pro-angiogenic factors (such as VEGF) toward cancer cells, endothelial cells, and immune cells. We primarily shed light on the potentiality of ethnopharmacology against tumor angiogenesis, particularly TCM. More research studies concerning the crosstalk between angiogenesis and TME remodeling from the perspective of botanical medicine are awaited.

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The Dual Effect of the BMP9–ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement?

Cited by 11 publications

References 169 publications

Endothelial Activin Receptor-Like Kinase 1 (ALK1) Regulates Myofibroblast Emergence and Peritubular Capillary Stability in the Early Stages of Kidney Fibrosis

Endothelial Activin Receptor-Like Kinase 1 (ALK1) Regulates Myofibroblast Emergence and Peritubular Capillary Stability in the Early Stages of Kidney Fibrosis

BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma

Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology

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