Emerging roles of the bone morphogenetic protein pathway in cancer: potential therapeutic target for kinase inhibition

Jiramongkolchai, Pawina; Owens, Philip; Hong, Charles C.

doi:10.1042/bst20160069

Cited by 39 publications

(57 citation statements)

References 154 publications

(199 reference statements)

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“…BMPs have divergent roles in cancer, acting as both suppressors and promoters of tumor progression under different circumstances. Based on the cell type and surrounding tumor microenvironment, BMPs take on differing actions in tumor biology (12). A positive correlation exists between BMP expression and clinical stages of cancer in human patients (13).…”

Section: Introductionmentioning

confidence: 99%

Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

et al. 2020

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The Bone Morphogenetic Protein (BMP) pathway is a member of the TGFβ signaling family and has complex roles in cancer. BMP signaling is rarely mutated and can be frequently overexpressed in many human cancers. The dichotomous role of BMPs as both tumor promoters and suppressors appears to be largely context based in both the cancer cell and the surrounding microenvironment. Myeloid cells including macrophages and neutrophils have been shown to be tumor promoting when stimulated from BMPs. We found that conditional deletion of BMPR1a in myeloid cells (LysMCre) restricts tumor progression in a syngeneic mouse prostate cancer model. Specific changes occurred in myeloid cells both in tumor bearing mice and tumor naïve mice throughout multiple tissues. We profiled myeloid subsets in the bone marrow, spleen and primary tumor and found myeloid BMPR1a loss altered the differentiation and lineage capability of distinct populations by histologic, flow cytometry and high dimensional mass cytometry analysis. We further confirmed the requirement for BMP signaling with pharmacologic inhibition of THP-1 and Raw264.7 activated into M2 macrophages with the BMP inhibitor DMH1. M2 polarized primary bone marrow derived cells from LysMCre BMPR1a knockout mice indicated a distinct requirement for BMP signaling in myeloid cells during M2 activation. These results indicate a unique necessity for BMP signaling in myeloid cells during tumor progression.

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Section: Introductionmentioning

confidence: 99%

Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

et al. 2020

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“…The complex functions of the BMP/FGF/TGF-β axis in development and disease have also been demonstrated by their dichotomous roles in various tumours and tumour stages [42] , suggesting that these molecules may be a valid target for cancer prevention and treatment.…”

Section: Othersmentioning

confidence: 99%

Targeting Developmental Pathways: The Achilles Heel of Cancer?

Dempke¹,

Fenchel

Uciechowski

et al. 2017

Oncology

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Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways.

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“…After the discovery that loss of BMPR1A leads to the development of Juvenile Polyposis [ 137 ], it was suggested that BMP signaling is tumor suppressive while classic TGF-β signaling is implicated in cancer pathogenesis. There is now increasing evidence that BMP signaling and BMPR2 play roles in tumor cell migration, metastasis, apoptosis, and local inflammation in a dynamic and complex manner, reviewed in [ 7 ]. For instance, breast cancer pathogenesis and BMP signaling appear to be related, with somewhat different results in human tissue versus mouse models.…”

Section: Bmpr2 Deficiency In Malignancymentioning

confidence: 99%

“…In the wake of the research that followed, the role of BMPR2 expanded beyond its origins in bone mineralization [ 3 ] to that of being a central key mediator of not only development but vascular homeostasis [ 4 , 5 ]. Beyond vascular biology, BMPR2 is necessary for development, organogenesis, and cancer pathogenesis [ 6 , 7 ]. Despite this, it remains strongly associated with its role in PAH pathogenesis, with an estimated 80% of familial and 20% of idiopathic PAH patients carrying a heterozygous BMPR2 mutation [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension

Andruska

Spiekerkoetter

2018

IJMS

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Since its association with familial pulmonary arterial hypertension (PAH) in 2000, Bone Morphogenetic Protein Receptor II (BMPR2) and its related signaling pathway have become recognized as a key regulator of pulmonary vascular homeostasis. Herein, we define BMPR2 deficiency as either an inactivation of the receptor, decreased receptor expression, or an impairment of the receptor’s downstream signaling pathway. Although traditionally the phenotypic consequences of BMPR2 deficiency in PAH have been thought to be limited to the pulmonary vasculature, there is evidence that abnormalities in BMPR2 signaling may have consequences in many other organ systems and cellular compartments. Revisiting how BMPR2 functions throughout health and disease in cells and organs beyond the lung vasculature may provide insight into the contribution of these organ systems to PAH pathogenesis as well as the potential systemic manifestation of PAH. Here we review our knowledge of the consequences of BMPR2 deficiency across multiple organ systems.

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Emerging roles of the bone morphogenetic protein pathway in cancer: potential therapeutic target for kinase inhibition

Cited by 39 publications

References 154 publications

Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

Targeting Developmental Pathways: The Achilles Heel of Cancer?

Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension

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