Vascular endothelial growth factor receptor‐1 in human cancer

Abstract

The human vascular endothelial growth factor receptor-1 (VEGFR-1, or Flt-1) is widely expressed in normal and pathologic tissue and contributes to the pathogenesis of both neoplastic and inflammatory diseases. In human cancer, VEGFR-1 mediated signaling is responsible for both direct tumor activation and angiogenesis. VEGFR-1 mediated activation of nonmalignant supporting cells, particularly stromal, dendritic, hematopoietic cells, and macrophages, is also likely important for cancer pathogenesis. VEGFR-1 is also hypothesized to enable the development of cancer metastases by means of activation and premetastatic localization in distant organs of bone marrow-derived hematopoietic progenitor cells, which express VEGFR-1. IMC-18F1 is a fully human IgG 1 antibody that binds to VEGFR-1 and has been associated with the inhibition of cancer growth in multiple in vitro and human tumor xenograft models. The preliminary results of phase 1 investigations have also indicated a favorable safety profile for IMC-18F1 at doses that confer antibody concentrations that are associated with relevant antitumor activity in preclinical models. Cancer 2010;116(4 suppl):1027-32.

Molecular mechanisms and clinical applications of angiogenesis

“…The precise role of the VEGFR-1 receptor (also known as FLT-1) in angiogenesis remains elusive 19,26 . VEGFR-1 exists both as a membrane-anchored signalling-competent form and as a soluble secreted form (also known as sFLT-1).…”

“…Because of its weak tyrosine kinase activity, VEGFR-1 may act as a decoy for VEGF, moderating the amount of free VEGF available to activate VEGFR-2 and explaining why VEGFR-1 loss results in vessel overgrowth 19 . However, intracellular VEGFR-1 signalling in angiogenic endothelial, stromal and myeloid cells stimulates pathological angiogenesis 26 . VEGFR-1 signalling also promotes the growth of VEGFR-1 + tumour cells in response to autocrine VEGF production in an angiogenesis-independent manner 27 , and upregulates MMP9 in endothelial cells at the premetastatic site.…”

The biological basis and clinical symptoms of CAR-T therapy-associated toxicites

“…Furthermore, other ‘universal’ targets for CAR-T cells include VEGF-1 (and VEGFR2), which are not only expressed on vascular endothelial cells, but also on the tumor cells of different lineages 90 . While positive pre-clinical 91,92 , including suppression of metastasis 92 were reported for CAR-T VEGF-1, the trials using CAR-T anti-VEGFR2 (NCT01218867) failed to show significant clinical activity.…”

Vascular endothelial growth factor receptors and the therapeutic targeting of angiogenesis in cancer: where do we go from here?

“…The VEGFR-1 tyrosine kinase is the only known cell surface receptor for VEGF-B and Placenta induced growth factor (PIGF) and also binds VEGF-A (Schwartz, Rowinsky, Youssoufi an, Pytowski, & Wu, 2010). VEGF-A binds VEGFR-1 with a higher affi nity than it does VEGFR-2, but the subsequent tyrosine kinase activity of VEGFR-1 is weaker than that of VEGFR-2 (Fischer, Mazzone, Jonckx, & Carmeliet, 2008;Waltenberger, Claesson-Welsh, Siegbahn, Shibuya, & Heldin, 1994).…”