Chondrosarcoma is the second most common sarcoma in bone malignancy and is characterized by a high metastatic potential. Angiogenesis is essential for the cancer metastasis. Endothelin-1 (ET-1) has been implicated in tumor angiogenesis and metastasis. However, the relationship of ET-1 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells is mostly unknown. Here, we found that the expression of ET-1 and VEGF were correlated with tumor stage and were significantly higher than that in the normal cartilage. Exogenous ET-1 with chondrosarcoma cells promoted VEGF expression and subsequently increased migration and tube formation in endothelial progenitor cells. ET-1 increased VEGF expression and angiogenesis through ETAR, integrin-linked kinase (ILK), Akt and hypoxia-inducible factor-1α (HIF-1α) signaling cascades. Knockdown of ET-1 decreased VEGF expression and also abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. In addition, in the xenograft tumor angiogenesis model, knockdown of ET-1 significantly reduced tumor growth and tumor-associated angiogenesis. Taken together, these results indicate that ET-1 occurs through ETAR, ILK and Akt, which in turn activates HIF-1α, resulting in the activation of VEGF expression and contributing to the angiogenesis and tumor growth of human chondrosarcoma cells.

Endothelin-1 promotes vascular endothelial growth factor-dependent angiogenesis in human chondrosarcoma cells.

https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1090&context=biochem_facpub

P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer

https://www.europeanurology.com/article/S0302-2838(13)00565-4/pdf/a-multicenter-phase-1-study-of-emd-525797-di17e6-a-novel-humanized-monoclonal-antibody-targeting-v-integrins-in-progressive-castration-resistant-prostate-cancer-with-bone-metastases-after-chemotherapy

A multicenter phase 1 study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody targeting αv integrins, in progressive castration-resistant prostate cancer with bone metastases after chemotherapy

Prostate cancer (PCa), like all other solid tumors, relies on angiogenesis for growth, progression, and the dissemination of tumor cells to other parts of the body. Despite data from in vitro and in vivo preclinical studies, as well as human specimen studies indicating the crucial role played by angiogenesis in PCa, angiogenesis inhibition in clinical settings has not shown significant benefits to patients, thus challenging the inclusion and usefulness of antiangiogenic agents for the treatment of PCa. However, one of the apparent reasons why these antiangiogenic agents failed to meet expectations in PCa can be due to the choice of the antiangiogenic agents, because the majority of these drugs target vascular endothelial growth factor-A (VEGFA) and its receptors. The other relevant causes might be inappropriate drug combinations, the duration of treatment, and the method of endpoint determination. In this review, we will first discuss the role of angiogenesis in PCa growth and progression. We will then summarize the different angiogenic growth factors that influence PCa growth dynamics and review the outcomes of clinical trials conducted with antiangiogenic agents in PCa patients and, finally, critically assess the current status and fate of antiangiogenic therapy in this disease.

Angiogenesis Inhibition in Prostate Cancer: An Update.

// Min-Huan Wu 1, 2 , Pei-Han Huang 3 , Mingli Hsieh 4 , Chun-Hao Tsai 5, 6 , Hsien-Te Chen 5, 7 , Chih-Hsin Tang 3, 6, 8 1 Physical Education Office, Tunghai University, Taichung, Taiwan 2 Sports Recreation and Health Management Continuing Studies, Tunghai University, Taichung, Taiwan 3 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 4 Department of Life Science, Tunghai University, Taichung, Taiwan 5 Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan 6 School of Medicine, China Medical University, Taichung, Taiwan 7 School of Chinese Medicine, China Medical University, Taichung, Taiwan 8 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan Correspondence to: Chih-Hsin Tang, email: chtang@mail.cmu.edu.tw Keywords: Endothelin-1, epithelial to mesenchymal transition, AMPK, Twist, miR-300 Received: June 16, 2016     Accepted: August 26, 2016     Published: September 02, 2016 ABSTRACT Chondrosarcoma is a malignant tumor of mesenchymal origin predominantly composed of cartilage-producing cells. This type of bone cancer is extremely resistant to radiotherapy and chemotherapy. Surgical resection is the primary treatment, but is often difficult and not always practical for metastatic disease, so more effective treatments are needed. In particular, it would be helpful to identify molecular markers as targets for therapeutic intervention. Endothelin-1 (ET-1), a potent vasoconstrictor, has been shown to enhance chondrosarcoma angiogenesis and metastasis. We report that ET-1 promotes epithelial–mesenchymal transition (EMT) in human chondrosarcoma cells. EMT is a key pathological event in cancer progression, during which epithelial cells lose their junctions and apical-basal polarity and adopt an invasive phenotype. Our study verifies that ET-1 induces the EMT phenotype in chondrosarcoma cells via the AMP-activated protein kinase (AMPK) pathway. In addition, we show that ET-1 increases EMT by repressing miR-300, which plays an important role in EMT-enhanced tumor metastasis. We also show that miR-300 directly targets Twist, which in turn results in a negative regulation of EMT. We found a highly positive correlation between ET-1 and Twist expression levels as well as tumor stage in chondrosarcoma patient specimens. Therefore, ET-1 may represent a potential novel molecular therapeutic target in chondrosarcoma metastasis.

/pdf/endothelin-1-promotes-epithelial-mesenchymal-transition-in-4arxmtj1ki.pdf

Endothelin-1 promotes epithelial-mesenchymal transition in human chondrosarcoma cells by repressing miR-300.

Antiangiogenic agents and endothelin antagonists in advanced castration resistant prostate cancer


 Effective treatments for Pancreatic ductal adenocarcinoma (PDAC) remain an urgent need. Integration of molecular PDAC subtypes into clinical trials could enable translational insights into how we might refine existing and emerging therapies to improve treatment options, yet this requires robust clinically suitable marker genes and a better understanding of subtype-related biology. Here, we deeply profiled the molecular composition of human PDAC epithelia and assessed differentially expressed genes for their ability to discriminate between subtypes and mirror their key biological traits. Using well-annotated resected & advanced biospecimens, we mapped the stromal and epithelial landscapes of PDAC subtypes by combining compartment-specific transcriptomics and proteomics with quantitative image analysis of a 42-marker IHC panel and single cell RNA sequencing analyses. The integrated profiling yielded a shortlist of 30 genes that were differentially expressed at both transcriptomic and proteomic levels, and across primary and metastatic sites. These were then scrutinized for their suitability as potential single gene subtype markers through association with subtype-related epithelial and stromal biology and clinical outcomes, and via practical considerations such as immunohistochemical staining quality and cell type-specific expression patterns. Since PDAC subtypes frequently co-occur intratumorally, we furthermore assessed complementarity of different subtype marker combinations and tested association of individual markers with regional subtype biology. Annexin A8 emerged as strong IHC-suitable marker gene of the basal/squamous subtype, that exhibited prognostic and predictive value. Concordantly, Annexin A8 expression was highly correlated with TP63, a master transcription factor for the squamous subtype, and CK5, a well-established basal cell marker. In tissue stains and single cell RNAseq data, Annexin A8 specifically marked malignant epithelia but was absent from adjacent normal acini and stroma cell populations. Annexin A8 expression in PDAC epithelia was spatially distinct from the known classical subtype biomarker GATA6, as well as Claudin 18, which was the top classical/pancreatic progenitor marker gene in our integrated multiOMIC analysis. Furthermore, Annexin A8high tumors as well as Annexin A8high intratumoral regions both recapitulated key biological traits of the basal-like/squamous PDAC subtype, such as increased EMT marker expression, proliferation, hypoxia, macrophage attraction and T cell repulsion. In conclusion, integrated proteogenomic characterization of PDAC subtypes and their tissue features uncovers complementary subtype marker pairs with clinical potential and provides insights into subtype-specific biology with implications in the development of future therapeutic approaches tailored to each PDAC subtype.
 Citation Format: Barbara T. Grünwald, Foram Vyas, Michael Geuenich, Nathan Chan, Ricardo Gonzalez, Kazeera Aliar, Niklas Krebs, Antoine Devisme, Geoffroy Andrieux, Gun Ho Jang, Grainne O'Kane, Julie Wilson, Jennifer Knox, Faiyaz Notta, Kieran Campbell, Steven Gallinger, Melanie Boerries, Sandra Fischer, Thomas Kislinger, Rama Khokha. Proteogenomic analysis of the PDAC epithelium reveals tissue markers of subtype identity and biology [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A031.

Abstract A031: Proteogenomic analysis of the PDAC epithelium reveals tissue markers of subtype identity and biology

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Antiangiogenic agents and endothelin antagonists in advanced castration resistant prostate cancer

Abstract A031: Proteogenomic analysis of the PDAC epithelium reveals tissue markers of subtype identity and biology