The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2Hi macrophages in breast cancer and neuroendocrine pancreatic tumors

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation and metastasis, which can offset the effects of chemotherapy, radiation, and anti-angiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and pro-tumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, anti-angiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2(hi)/VegfA(hi) macrophages in the tumor microenvironment of metastasis (TMEM). The anti-tumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by pro-tumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients.

Macrophage regulation of tumor angiogenesis: implications for cancer therapy

Michele De Palma, Mario Leonardo Squadrito

This article reviews the evidence for macrophages playing an important role in the regulation of tumor angiogenesis. Findings in mouse models show that macrophages promote angiogenesis in tumors both by producing excessive amounts of proangiogenic factors and by physically assisting sprouting blood vessels to augment the complexity of the intra-tumoral vascular network. Recent studies however suggest that macrophages may be dispensable for the initiation of angiogenesis in tumors. Rather, these cells express proangiogenic programs that enhance the complexity of the tumor-associated vasculature, leading to aberrant, plethoric and dysfunctional angiogenesis. Gene expression and cell depletion studies further indicate that tumor-associated macrophages (TAMs) comprise phenotypically and functionally distinct subsets. This may reflect "education" of the macrophage phenotype by signals in some areas of the tumor microenvironment and/or TAM subsets derived from distinct macrophage precursors. Among the better characterized TAM subsets are the proangiogenic (TIE2(+)) and the angiostatic/inflammatory (CD11c(+)) macrophages, which coexist in tumors. Such antagonizing TAM subsets occupy distinct niches in the tumor microenvironment and are present at ratios that vary according to the tumor type and grade. Specifically targeting TAMs or reprogramming them from a proangiogenic to an angiostatic function may "normalize" the tumor vasculature and improve the efficacy of various anticancer therapies, including radiotherapy, chemotherapy and vascular-disrupting agents.

2011

Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation

Anguraj Sadanandam, Stephan Wullschleger

BACKGROUND: Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A modulates certain phenotypes associated with tumour progression, angiogenesis and metastasis through various other molecular factors and signalling proteins. METHODS AND RESULTS: In this study, we show that human pancreatic cancer cell lines secrete the extracellular domain (ECD) of SEMA5A (SEMA5A-ECD) and overexpression of mouse Sema5A-ECD in Panc1 cells (not expressing SEMA5A; Panc1-Sema5-AECD; control cells - Panc1-control) significantly increases their invasion in vitro via enhanced ERK phosphorylation. Interestingly, orthotopic injection of Panc1-Sema5A-ECD cells into athymic nude mice results in a lower primary tumour burden, but enhances the micrometastases to the liver as compared with Panc1-control cells. Furthermore, there is a significant increase in proliferation of endothelial cells treated with conditioned media (CM) from Panc1-Sema5A-ECD cells and a significant increase in microvessel density in Panc1-Sema5A-ECD orthotopic tumours compared with those from Panc1-control cells, suggesting that the increase in liver micrometastases is probably due to increased tumour angiogenesis. In addition, our data demonstrate that this increase in endothelial cell proliferation by Sema5A-ECD is mediated through the angiogenic molecules - interleukin-8 and vascular endothelial growth factor. CONCLUSION: Taken together, these results suggest that a bioactive, secreted form of Sema5A-ECD has an intriguing and potentially important role in its ability to enhance pancreatic tumour invasiveness, angiogenesis and micrometastases. British Journal of Cancer (2012) 107, 501-507. doi: 10.1038/bjc.2012.298 www.bjcancer.com Published online 10 July 2012 (C) 2012 Cancer Research UK

Nature Publishing Group2012

Low Doses of Ionizing Radiation Promote Tumor Growth and Metastasis by Enhancing Angiogenesis

Natsuko Imaizumi

Radiotherapy is a widely used treatment option in cancer. However, recent evidence suggests that doses of ionizing radiation (IR) delivered inside the tumor target volume, during fractionated radiotherapy, can promote tumor invasion and metastasis. Furthermore, the tissues that surround the tumor area are also exposed to low doses of IR that are lower than those delivered inside the tumor mass, because external radiotherapy is delivered to the tumor through multiple radiation beams, in order to prevent damage of organs at risk. The biological effects of these low doses of IR on the healthy tissue surrounding the tumor area, and in particular on the vasculature remain largely to be determined. We found that doses of IR lower or equal to 0.8 Gy enhance endothelial cell migration without impinging on cell proliferation or survival. Moreover, we show that low-dose IR induces a rapid phosphorylation of several endothelial cell proteins, including the Vascular Endothelial Growth Factor (VEGF) Receptor-2 and induces VEGF production in hypoxia mimicking conditions. By activating the VEGF Receptor-2, low-dose IR enhances endothelial cell migration and prevents endothelial cell death promoted by an anti-angiogenic drug, bevacizumab. In addition, we observed that low-dose IR accelerates embryonic angiogenic sprouting during zebrafish development and promotes adult angiogenesis during zebrafish fin regeneration and in the murine Matrigel assay. Using murine experimental models of leukemia and orthotopic breast cancer, we show that low-dose IR promotes tumor growth and metastasis and that these effects were prevented by the administration of a VEGF receptor-tyrosine kinase inhibitor immediately before IR exposure. These findings demonstrate a new mechanism to the understanding of the potential pro-metastatic effect of IR and may provide a new rationale basis to the improvement of current radiotherapy protocols.