Question

Why do Inhibitors of the PDGF receptor work better in “regression models” as opposed to "prevention models"?

Answer 1

The role of PDGF in carcinogenesis was initially demonstrated by the fact that v-sis oncogene encodes a PDGF-B-like protein. Both v-sis and its cellular counterpart c-sis transform cultured cells through an autocrine mechanism. In the last two decades, it was shown that PDGF and PDGFR are involved in human cancer development and progression through autocrine stimulation of tumor cell growth. In addition to the autocrine stimulation of tumor growth, PDGF signaling exerts paracrine stimulation on stromal cells and maybe the best certified example is tumor-associated angiogenesis. PDGF and PDGFR are involved in cancer by mutations that may lead to increased PDGF-levels or PDGFR activity, but retaining the structure and functions of these proteins [19]. The mode of action of PDGF and PDGFR in cancer development is largely autocrine and cell-autonomous as compared with the normal development where the mode of action is predominantly paracrine. PDGF play minimum three roles that may lead to tumor development, including: (i) autocrine stimulation of cancer cells; (ii) stimulation of angiogenesis; (iii) control of tumor interstitial pressure. Blockade of autocrine stimulation of tumor growth by blocking PDGFR in cell lines and xenograft models showed consistent positive results in dermatofibrosarcoma protuberans, prostate cancer, ovarian cancer and gliomas (reviewed in [26]). In an experimental model it was shown that VEGF-null cells require PDGFR? for the recruitment of fibroblast in the tumor stroma.