Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti-cancer strategies

Abstract

Tumor growth relies on oxygen and blood supply depending on neo-vascularization. This process is mediated by the Vascular Endothelial Growth Factor (VEGF) in many tumors. This paradigm has led to the development of specific therapeutic approaches targeting VEGF or its receptors. Despite their promising effects, these strategies have not improved overall survival of patients suffering from different cancers compared to standard therapies. We hypothesized that the existence of anti-angiogenic forms of VEGF VEGFxxxb which are still present in many tumors limit the therapeutic effects of the anti-VEGF antibodies bevacizumab/Avastin (BVZ). To test this hypothesis, we generated renal cell carcinoma cells (RCC) expressing VEGF165b. The incidence of tumors xenografts generated in nude mice and their growth were inferior to those obtained with control cells. Whereas BVZ had no effect on control tumors, it slowed-down the growth of tumor generated with VEGF165b expressing cells. A prophylactic immunization against the domain discriminating VEGF from VEGFxxxb isoforms inhibited the growth of tumor generated with two different syngenic tumor cell lines (melanoma (B16 cells) and RCC (RENCA cells)). Purified immunoglobulins from immunized mice also slowed-down tumor growth of human RCC xenografts in nude mice, producing a potent effect compared to BVZ in this model. Furthermore, down-regulating the serine-arginine-rich splicing factor 1 (SRSF1) or masking SRSF1 binding sites by 2’O-Methyl RNA resulted in the increase of the VEGFxxxb/VEGF ratio. Therefore, a vaccine approach, specific antibodies against pro-angiogenic forms of VEGF, or increasing the VEGFxxxb/VEGF ratio may represent new prophylactic or pro-active anti-cancer strategies.

Gene editing of the extra domain A positive fibronectin in various tumors, amplified the effects of CRISPR/Cas system on the inhibition of tumor progression

“…To some extent, tumors can be considered ecological systems in which Darwinian evolution applies [ 2 , 5 ], and therefore, the modification of the tumor microenvironment may be an alternative approach to the inhibition of tumor progression [ 8 ], in order to prolong the survival periods. In tumor microenvironment, paracrine or autocrine molecules participate in maintaining favorable conditions for the propagation of tumor cells, such as the extracellular matrix (ECM) component extra domain A positive fibronectin (EDA+FN), as well as the vascular endothelial growth factor A isoforms ( VEGF -Axxx), the pro-oncogenic isoforms generated by the alternative splicing of FN or VEGF genes [ 9 , 10 ], respectively. These alternative spliced isoforms are always absent in normal adult tissues, but exclusively expressed in tumor, wound healing and inflammation.…”

“…These alternative spliced isoforms are always absent in normal adult tissues, but exclusively expressed in tumor, wound healing and inflammation. On this basis, most types of tumor cells could attenuate the physical barriers formed by the ECM [ 11 , 12 ], or vascularize the tumor tissue in advance [ 10 ]. By targeting those paracrine or autocrine molecules spreading over the tumor microenvironment, it may not be necessary to eradicate all tumor cells, but modify a part of them, primarily the sub-populations supporting the propagation of the whole community [ 13 ].…”

Enhanced bioactivity and efficient delivery of quercetin through nanoliposomal encapsulation using rice bran phospholipids

“…Aberrant angiogenesis promotes cancer cell growth and proliferation (metastasis), as these processes are mainly dependent on vascular supply. Use of angiosuppressive compounds to inhibit neovascularization can potentially prevent or reduce such proliferations, thus the risk of cancer . Meanwhile, pro‐angiogenesis treatment is gaining attention, not just for wound healing but also for tissue and organ regeneration, especially for damaged or abnormal cardiovascular system and age‐related ischemia …”

“…Use of angiosuppressive compounds to inhibit neovascularization can potentially prevent or reduce such proliferations, thus the risk of cancer. [53][54][55] Meanwhile, pro-angiogenesis treatment is gaining attention, not just for wound healing but also for tissue and organ regeneration, especially for damaged or abnormal cardiovascular system and age-related ischemia. [56][57][58][59]…”

Co‐ordinated expression of the VEGF system components in granulosa cells to develop a proangiogenic autocrine milieu during ovarian follicle development

“…In contrast, if splicing happens at the distal‐site of exon 8, antiangiogenic isoforms are produced, VEGFxxxb (Harper & Bates, ; Nowak et al, ). The mechanisms that regulate the expression of either type of VEGF isoform have been elucidated in cancer tissue (Guyot et al, ; Mavrou & Oltean, ; Oltean et al, , Gammons et al, ). In this tissue VEGFxxxa and VEGFxxxb production is dependent on serine–arginine‐rich splicing factors (SRSF).…”