Faculty Opinions recommendation of Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells.

Forty years ago, Judah Folkman (Folkman. N Engl J Med 285: 1182–1186, 1971) proposed that tumor growth might be controlled by limiting formation of new blood vessels (angiogenesis) needed to supply a growing tumor with oxygen and nutrients. To this end, numerous “antiangiogenic” agents have been developed and tested for therapeutic efficacy in cancer patients, including prostate cancer (CaP) patients, with limited success. Despite the lack of clinical efficacy of lead anti-angiogenic therapeutics in CaP patients, recent published evidence continues to support the idea that prostate tumor vasculature provides a reasonable target for development of new therapeutics. Particularly relevant to antiangiogenic therapies targeted to the prostate is the observation that specific hormones can affect the survival and vascular function of prostate endothelial cells within normal and malignant prostate tissues. Here, we review the evidence demonstrating that both androgen(s) and vitamin D significantly impact the growth and survival of endothelial cells residing within prostate cancer and that systemic changes in circulating androgen or vitamin D drastically affect blood flow and vascularity of prostate tissue. Furthermore, recent evidence will be discussed about the expression of the receptors for both androgen and vitamin D in prostate endothelial cells that argues for direct effects of these hormone-activated receptors on the biology of endothelial cells. Based on this literature, we propose that prostate tumor vasculature represents an unexplored target for modulation of tumor growth. A better understanding of androgen and vitamin D effects on prostate endothelial cells will support development of more effective angiogenesis-targeting therapeutics for CaP patients.

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Targeting the SHP2 phosphatase promotes vascular damage and inhibition of tumor growth

10.1101/2020.10.06.327882 ◽

2020 ◽

Author(s):

Yuyi Wang ◽

Ombretta Salvucci ◽

Hidetaka Ohnuki ◽

Andy D. Tran ◽

Taekyu Ha ◽

...

Keyword(s):

Endothelial Cells ◽

Tumor Growth ◽

Tyrosine Kinases ◽

Vascular Endothelial Cells ◽

Tyrosine Phosphatase ◽

Tumor Hypoxia ◽

Blood Perfusion ◽

Tumor Vasculature ◽

Immune Checkpoints ◽

Tumor Vascularity

AbstractThe tyrosine phosphatase SHP2 is oncogenic in cancers driven by receptor-tyrosine-kinases, and SHP2 inhibition reduces tumor growth. Here, we report that SHP2 is an essential promoter of endothelial cell survival and growth in the remodeling tumor vasculature. Using genetic and chemical approaches to inhibit SHP2 activity in endothelial cells, we show that SHP2 inhibits pro-apoptotic STAT3 and stimulates proliferative ERK1/2 signaling. Systemic SHP2 inhibition in mice bearing tumors selected for SHP2-independent tumor-cell growth, promotes degeneration of the tumor vasculature and blood extravasation; reduces tumor vascularity and blood perfusion; and increases tumor hypoxia and necrosis. Reduction of tumor growth ensues, independent of SHP2 targeting in the tumor cells, blocking immune checkpoints or recruiting anti-tumor macrophages. We also show that inhibiting the Angiopoietin/TIE2/AKT cascade magnifies the vascular and anti-tumor effects of SHP2 inhibition by blocking tumor endothelial AKT signaling, not a target of SHP2. Since the SHP2 and Ang2/TIE2 pathways are active in vascular endothelial cells of human melanoma and colon carcinoma, SHP2 inhibitors alone or with Ang2/Tie2 inhibitors hold promise to effectively target the tumor endothelium.

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Inhibition of Tumor Growth by RGD Peptide Directed Delivery of Truncated Tissue Factor to the Tumor Vasculature.

Blood ◽

10.1182/blood.v104.11.1934.1934 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1934-1934

Author(s):

Torsten Kessler ◽

Ralf Bieker ◽

Teresa Padro ◽

Federico Herrera ◽

Sandra Ruiz ◽

...

Keyword(s):

Endothelial Cells ◽

Fusion Protein ◽

Tumor Growth ◽

Tissue Factor ◽

Tumor Vasculature ◽

Binding Activity ◽

In Vivo Studies ◽

Binding Assays ◽

Tumor Vessels

Abstract Selective activation of blood coagulation in tumor vessels with subsequent tumor infarction is a promising anticancer strategy. To this end, a fusion protein consisting of the extracellular domain of tissue factor (truncated tissue factor, tTF) was fused to the peptide GRGDSP selectively targeting avb3 and avb5 integrins on tumor endothelial cells. The fusion protein tTF-RGD retained its thrombogenic and integrin binding activity as demonstrated by coagulation assays and binding assays with purified avb3 and endothelial cells. In vivo studies in mice bearing established human adenocarcinomas (CCL185), human melanoma (M21) and human fibrosarcoma (HT1080) revealed that i.v. administration of tTF-RGD induced partial or complete thrombotic occlusion of tumor vessels as indicated by histological analysis. Furthermore, treatment studies showed that tTF-RGD but not untargeted tTF induced significant tumor growth retardation or regression in all three types of solid tumors in mice without apparent side effects such as thrombosis in liver, kidney, heart or lung. Thus, selective thrombosis in the tumor vasculature induced by tTF-RGD may be a promising strategy for the treatment of cancer.

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Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells

Journal of Experimental Medicine ◽

10.1084/jem.20100951 ◽

2011 ◽

Vol 208 (7) ◽

pp. 1351-1358 ◽

Cited By ~ 21

Author(s):

Edwina Naik ◽

Lorraine A. O'Reilly ◽

Marie-Liesse Asselin-Labat ◽

Delphine Merino ◽

Ann Lin ◽

...

Keyword(s):

Tumor Growth ◽

Anticancer Agents ◽

Tumor Vasculature ◽

Vascular Endothelial ◽

Drug Induced ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Proapoptotic Protein ◽

Induced Apoptosis ◽

Endothelial Growth Factor

For malignant growth, solid cancers must stimulate the formation of new blood vessels by producing vascular endothelial growth factor (VEGF-A), which is required for the survival of tumor-associated vessels. Novel anticancer agents that block VEGF-A signaling trigger endothelial cell (EC) apoptosis and vascular regression preferentially within tumors, but how the ECs die is not understood. In this study, we demonstrate that VEGF-A deprivation, provoked either by drug-induced tumor shrinkage or direct VEGF-A blockade, up-regulates the proapoptotic BH3 (Bcl-2 homology 3)-only Bcl-2 family member Bim in ECs. Importantly, the tumor growth inhibitory activity of a VEGF-A antagonist required Bim-induced apoptosis of ECs. These findings thus reveal the mechanism by which VEGF-A blockade induces EC apoptosis and impairs tumor growth. They also indicate that drugs mimicking BH3-only proteins may be exploited to kill tumor cells not only directly but also indirectly by ablating the tumor vasculature.

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A novel peptide from human apolipoprotein(a) inhibits angiogenesis and tumor growth by targeting c-Src phosphorylation in VEGF-induced human umbilical endothelial cells

International Journal of Cancer ◽

10.1002/ijc.24027 ◽

2009 ◽

Vol 124 (4) ◽

pp. 843-852 ◽

Cited By ~ 42

Author(s):

Zheng-Fang Yi ◽

Sung-Gook Cho ◽

Hui Zhao ◽

Yuan-yuan Wu ◽

Jian Luo ◽

...

Keyword(s):

Endothelial Cells ◽

Tumor Growth ◽

Human Apolipoprotein ◽

Apolipoprotein A

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Bone marrow-derived cells are recruited by the melanoma tumor with endothelial cells contributing to tumor vasculature

Clinical & Translational Oncology ◽

10.1007/s12094-016-1515-z ◽

2016 ◽

Vol 19 (1) ◽

pp. 125-133 ◽

Cited By ~ 5

Author(s):

R. Bonfim-Silva ◽

L. E. B. Souza ◽

F. U. F. Melo ◽

V. C. Oliveira ◽

D. A. R. Magalhães ◽

...

Keyword(s):

Bone Marrow ◽

Endothelial Cells ◽

Tumor Vasculature ◽

Melanoma Tumor ◽

Bone Marrow Derived Cells

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A Novel Bispecific Antibody Targeting EGFR and VEGFR2 Is Effective against Triple Negative Breast Cancer via Multiple Mechanisms of Action

Cancers ◽

10.3390/cancers13051027 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1027

Author(s):

Nishant Mohan ◽

Xiao Luo ◽

Yi Shen ◽

Zachary Olson ◽

Atul Agrawal ◽

...

Keyword(s):

Endothelial Cells ◽

Tumor Growth ◽

Mechanisms Of Action ◽

Breast Cancers ◽

Single Chain ◽

Cancer Cell Growth ◽

Anti Tumor Activity ◽

Enhance Tumor Growth

Both EGFR and VEGFR2 frequently overexpress in TNBC and cooperate with each other in autocrine and paracrine manner to enhance tumor growth and angiogenesis. Therapeutic mAbs targeting EGFR (cetuximab) and VEGFR2 (ramucirumab) are approved by FDA for numerous cancer indications, but none of them are approved to treat breast cancers. TNBC cells secrete VEGF-A, which mediates angiogenesis on endothelial cells in a paracrine fashion, as well as promotes cancer cell growth in autocrine manner. To disrupt autocrine/paracrine loop in TNBC models in addition to mediating anti-EGFR tumor growth signaling and anti-VEGFR2 angiogenic pathway, we generated a BsAb co-targeting EGFR and VEGFR2 (designated as anti-EGFR/VEGFR2 BsAb), using publicly available sequences in which cetuximab IgG backbone is connected to the single chain variable fragment (scFv) of ramucirumab via a glycine linker. Physiochemical characterization data shows that anti-EGFR/VEGFR2 BsAb binds to both EGFR and VEGFR2 in a similar binding affinity comparable to parental antibodies. Anti-EGFR/VEGFR2 BsAb demonstrates in vitro and in vivo anti-tumor activity in TNBC models. Mechanistically, anti-EGFR/VEGFR2 BsAb not only directly inhibits both EGFR and VEGFR2 in TNBC cells but also disrupts autocrine mechanism in TNBC xenograft mouse model. Furthermore, anti-EGFR/VEGFR2 BsAb inhibits ligand-induced activation of VEGFR2 and blocks paracrine pathway mediated by VEGF secreted from TNBC cells in endothelial cells. Collectively, our novel findings demonstrate that anti-EGFR/VEGFR2 BsAb inhibits tumor growth via multiple mechanisms of action and warrants further investigation as a targeted antibody therapeutic for the treatment of TNBC.

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