The impact of vascular structure and function on tumor growth, retinopathy, and antiangiogenic therapy

Abstract: Tumors produce multiple angiogenic factors to stimulate neovascularization that is essential for tumor growth, invasion and metastasis. Despite the known angiogenic functions of each individual factor, the interplay between these angiogenic factors in the tumor local environment and in modulation of the host functions remain poorly understood. This thesis addresses these important and complex issues using various in vitro and in vivo experimental models. The findings from these studies provide mechanistic insights on the of complex interplay between various angiogenic factors and on the systemic impact of these tumor-derived factors on the host. In paper I, we showed one of the first examples of two unrelated angiogenic factors, i.e., FGF-2 and PDGF-BB that reciprocally modulate tumor angiogenesis and metastasis. We found that FGF-2 markedly upregulates the expression levels of PDGFRα and β in endothelial cells, leading to the hypersensitive response of these cells toward PDGF-BB stimulation. Reciprocally, PDGF-BB is also able to upregulate the expression level of FGFR-1 in perivascular cells. The angiogenic synergism and vascular remodeling by these two factors markedly accelerates tumor growth rates, leading to an invasive phenotype in a mouse xenograft tumor model. In paper II, we describe a negative interplay between two angiogenic factors that significantly modulate the number and structure of tumor blood vessels. PlGF could negatively modulate VEGF functions by the formation of heterodimers during their synthesis in the same cell. We show that the PlGF-VEGF heterodimers are less potent than VEGF homodimers and thus significantly reduce the angiogenic activity of VEGF. Surprisingly, we found that modulation of the VEGF-induced angiogenic activity by PlGF markedly normalize tumor vessels. PlGF-induced vascular normalization may imply increased therapeutic efficacy of antiangiogenic drugs. In paper III, we showed that tumor-derived VEGF and PlGF can enter into the circulation and systemically impair vascular functions of other tissue and organs. In this paper, we proposed a new mechanism of cancer-associated retinopathy caused by tumor-derived angiogenic factors. Unlike vasculatures distributed in other tissues, the retinal vasculature predominantly expresses VEGFR1, but lacks a detectable level of VEGFR2. Tumor-derived VEGF and PlGF significantly ablate vascular pericytes, leading to increased leakiness of the retinal vasculature. These findings suggest that targeting tumor-derived VEGF, PlGF or other related angiogenic factors might provide a new therapeutic strategy for the treatment of cancer-associated retinopathy, which otherwise remains untreatable. In paper IV, we discovered a new mechanism underlying the combination therapy between antiangiogenic drugs and chemotherapeutics. Based on preclinical findings, we propose that decreased chemotoxicity by antiangiogenic drugs might significantly contribute to survival advantages of patient receiving a combination of these two classes of drugs. We have also rationalized the optimal delivery of these two drugs by using a sequential procedure rather than a simultaneous schedule as currently recommended in clinical settings. Taken together, this thesis work reveals several novel mechanisms of tumor angiogenesis and provides novel information of antiangiogenic therapy, which can be further optimized based on the work reported in this thesis. This thesis work represents translational and that mechanistic studies which can lead to clinically meaningful implications and our eventual goal is to improve survival and the quality of life for millions of cancer patients.