title: Escape from tumor dormancy and time to angiogenic switch as mitigated by tumor-induced stimulation of stroma.
abstract: A variety of mechanisms have been proposed to explain "cancer without disease", the state of tumor dormancy, characterized by balance in cell proliferation and cell death within a tumor. Here we have investigated a theoretical construct, whereby one of such mechanisms, the time to induction of angiogenesis, or "angiogenic switch", is mitigated by the degree of stromal stimulation by the tumor. We tested this hypothesis and its implications by introducing a mathematical model that captures how angiogenesis regulators, released from the platelet clot, contribute to formation of normal vasculature. We then modified the model to introduce tumor-induced increase in production of angiogenesis regulators and were able to simulate pathological angiogenesis. Through varying parameters governing the degree of tumor-induced stromal stimulation, we were able to qualitatively replicate experimentally observed growth curves for both dormant and actively growing tumors of breast cancer and liposarcoma. In fact, variation of very few parameters was sufficient to replicate any experimentally observed time to angiogenic switch in the available data. Finally, we investigated the effects of tighter binding isoforms of angiogenesis stimulators on neovasculature formation and tumor growth, which may provide an explanation for variations in angiogenesis -dependence in tumors of different tissue origin.
authors.affiliation: Floating Hospital for Children at Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA; Mathematical, Computational and Modeling Sciences Center, Arizona State University, Tempe, AZ 85287, USA. Electronic address: ikareva@asu.edu.
authors.forename: Irina
authors.initials: I
authors.lastname: Kareva
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008080:Liposarcoma / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology
keywords: Angiogenesis regulators; Angiogenic switch; Escape from tumor dormancy; Mathematical model; VEGF isoforms