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BMP Signaling and TGF-β Family in Cancer Development

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 11652

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Special Issue Editor

Dr. Tomohiko Fukuda

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Guest Editor

Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan
Interests: ovarian cancer; endometrial cancer; BMP; TGFβ; EMT; cancer stem cells; molecular-targeted therapies

Special Issue Information

Dear Colleagues,

Transforming growth factor-β (TGF-β) promotes cancer metastasis via epithelial–mesenchymal transition (EMT) induction. In addition, other TGF-β family ligands, such as bone morphogenetic proteins (BMPs), have been shown to play important roles in cancer development. In glioblastoma and multiple myeloma, BMP is a tumor suppressor by inducing differentiation and apoptosis, respectively. On the other hand, BMP promotes the development of colon and ovarian cancer by enhancing cell proliferation and induction of EMT. Since BMP also induces angiogenesis by interacting with ALK1, dalantercept, a soluble ALK1 ligand trap, has been developed as a new angiogenesis inhibitor for cancer patients. Furthermore, the tumor-promoting effects of GREM1, a BMP antagonist, have also been elucidated in several types of cancer. These findings suggest that BMP signaling is an attractive therapeutic target in cancer. Under this perspective, this Special Issue aims to describe the current advances in basic and translational research that focuses on BMPs and other TGF-β family ligands in cancer development.

Dr. Tomohiko Fukuda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

BMP
BMP antagonists
TGF-β family ligands
cancer
EMT
cancer stem cells
angiogenesis

Published Papers (4 papers)

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Research

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14 pages, 7607 KiB

Open AccessArticle

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

by Han Chen, Kouki Nio, Hong Tang, Taro Yamashita, Hikari Okada, Yingyi Li, Phuong Thi Bich Doan, Ru Li, Junyan Lv, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Honda and Shuichi Kaneko

Int. J. Mol. Sci. 2022, 23(3), 1475; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031475 - 27 Jan 2022

Cited by 14 | Viewed by 3328

Abstract

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. Full article

(This article belongs to the Special Issue BMP Signaling and TGF-β Family in Cancer Development)

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13 pages, 3142 KiB

Open AccessArticle

Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment

by Francesco Dituri, Serena Mancarella, Grazia Serino, Nada Chaoul, Luigi Giovanni Lupo, Erica Villa, Isabel Fabregat and Gianluigi Giannelli

Int. J. Mol. Sci. 2021, 22(21), 11765; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111765 - 29 Oct 2021

Cited by 8 | Viewed by 2101

Abstract

The balance between anti-tumor and tumor-promoting immune cells, such as CD4+ Th1 and regulatory T cells (Tregs), respectively, is assumed to dictate the progression of hepatocellular carcinoma (HCC). The transforming growth factor beta (TGFβ) markedly shapes the HCC microenvironment, regulating the activation state of multiple leukocyte subsets and driving the differentiation of cancer associated fibroblasts (CAFs). The fibrotic (desmoplastic) reaction in HCC tissue strongly depends on CAFs activity. In this study, we attempted to assess the role of TGFβ on transendothelial migration of Th1-oriented and Treg-oriented CD4+ T cells via a direct or indirect, CAF-mediated mechanisms, respectively. We found that the blockage of TGFβ receptor I-dependent signaling in Tregs resulted in impaired transendothelial migration (TEM) of these cells. Interestingly, the secretome of TGFβ-treated CAFs inhibited the TEM of Tregs but not Th1 cells, in comparison to the secretome of untreated CAFs. In addition, we found a significant inverse correlation between alpha-SMA and FoxP3 (marker of Tregs) mRNA expression in a microarray analysis involving 78 HCCs, thus suggesting that TGFβ-activated stromal cells may counteract the trafficking of Tregs into the tumor. The apparent dual behavior of TGFβ as both pro- and anti-tumorigenic cytokines may add a further level of complexity to the mechanisms that regulate the interactions among cancerous, stromal, and immune cells within HCC, as well as other solid tumors, and contribute to better manipulation of the TGFβ signaling as a therapeutic target in HCC patients. Full article

(This article belongs to the Special Issue BMP Signaling and TGF-β Family in Cancer Development)

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Review

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11 pages, 1838 KiB

Open AccessReview

Multifaceted Functions of TWSG1: From Embryogenesis to Cancer Development

by Eri Suzuki and Tomohiko Fukuda

Int. J. Mol. Sci. 2022, 23(21), 12755; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112755 - 22 Oct 2022

Cited by 2 | Viewed by 2000

Abstract

Bone morphogenetic proteins (BMPs) play an important role in development. Twisted gastrulation BMP signaling modulator 1 (TWSG1) was initially identified as a regulator of the dorsoventral axis formation in Drosophila. The mechanism of BMP signaling modulation by TWSG1 is complex. TWSG1 inhibits BMP signaling by binding to BMP ligands including BMP4, whereas it enhances signaling by interacting with Chordin, a BMP antagonist. Therefore, TWSG1 can act as both a BMP agonist and antagonist. TWSG1 has various functions ranging from embryogenesis to cancer progression. TWSG1 knockout mice showed neural, craniofacial, and mammary defects. TWSG1 also regulated erythropoiesis and thymocyte development. Furthermore, the relationship between TWSG1 and cancer has been elucidated. Allelic loss of TWSG1 was detected in colorectal cancer. TWSG1 expression was upregulated in papillary thyroid carcinoma and glioblastoma but downregulated in gastric and endometrial cancers. TWSG1 suppressed BMP7-enhanced sphere formation and migration in endometrial cancer cells, indicating its tumor-suppressive role. Further studies are required to clarify the TWSG1 function and its association with BMP signaling in cancer development. Finally, TWSG1 is abundantly expressed in human and mouse ovaries and sustains follicular growth in rodent ovaries. Thus, TWSG1 has various functions ranging from fertility to cancer. Therefore, TWSG1 signaling modulation may be beneficial in treating specific diseases such as cancer. Full article

(This article belongs to the Special Issue BMP Signaling and TGF-β Family in Cancer Development)

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17 pages, 1819 KiB

Open AccessReview

Metastatic Voyage of Ovarian Cancer Cells in Ascites with the Assistance of Various Cellular Components

by Kaname Uno, Shohei Iyoshi, Masato Yoshihara, Kazuhisa Kitami, Kazumasa Mogi, Hiroki Fujimoto, Mai Sugiyama, Yoshihiro Koya, Yoshihiko Yamakita, Akihiro Nawa, Tomohiro Kanayama, Hiroyuki Tomita, Atsushi Enomoto and Hiroaki Kajiyama

Int. J. Mol. Sci. 2022, 23(8), 4383; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084383 - 15 Apr 2022

Cited by 16 | Viewed by 3582

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and has a unique metastatic route using ascites, known as the transcoelomic root. However, studies on ascites and contained cellular components have not yet been sufficiently clarified. In this review, we focus on the significance of accumulating ascites, contained EOC cells in the form of spheroids, and interaction with non-malignant host cells. To become resistant against anoikis, EOC cells form spheroids in ascites, where epithelial-to-mesenchymal transition stimulated by transforming growth factor-β can be a key pathway. As spheroids form, EOC cells are also gaining the ability to attach and invade the peritoneum to induce intraperitoneal metastasis, as well as resistance to conventional chemotherapy. Recently, accumulating evidence suggests that EOC spheroids in ascites are composed of not only cancer cells, but also non-malignant cells existing with higher abundance than EOC cells in ascites, including macrophages, mesothelial cells, and lymphocytes. Moreover, hetero-cellular spheroids are demonstrated to form more aggregated spheroids and have higher adhesion ability for the mesothelial layer. To improve the poor prognosis, we need to elucidate the mechanisms of spheroid formation and interactions with non-malignant cells in ascites that are a unique tumor microenvironment for EOC. Full article

(This article belongs to the Special Issue BMP Signaling and TGF-β Family in Cancer Development)

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