Targeting Angiogenesis and Tumor Microenvironment in Metastatic Colorectal Cancer: Role of Aflibercept
New molecules targeting angiogenesis and crosstalks between angiogenesis and tumor microenvironment. Simplified and schematic view of how multiple cells contribute to the VEGF and PlGF pool in the tumor microenvironment. The tumor microenvironment (TME) consists of soluble molecules, immune, nonimmune fibroblastic, vascular, and malignant cells that interact in a paracrine and autocrine fashion to promote cancer growth and metastasis. Hypoxia is the most potent stimulus for inducing the main angiogenic factors, VEGF and PlGF. Myeloid derived suppressor cells (MDSCs) might confer resistance to therapies that target VEGF by secreting additional proangiogenic factors and specifically by expressing VEGFR-1 (also known as FLT1). PlGF signals directly through VEGFR-1 in various cell types, including endothelial cells, angiogenesis-competent myeloid progenitors, macrophages, and tumour cells and thereby promotes tumour growth and the formation of the premetastatic niche. A substantial fraction of tumours is resistant or escapes antiangiogenic inhibitors that target VEGF-A signalling (bevacizumab) through therapy-induced injury, metabolic changes, inflammation, and possibly expansion of MDSCs. Differently from other antiangiogenic drugs, aflibercept targeting PlGF should reduce the source of the compensatory upregulation of angiogenic factors by inhibiting immune cells recruitment and/or polarization and the release of angiogenic factors by tumour and vascular cells. Regorafenib is a multikinase inhibitor against selected tyrosine kinases and signal transduction VEGFR2-3/RAF/MEK/ERK pathway.