Treating cancers by targeting their blood vessels is based on sound scientific rationale and has been shown to be highly effective against transplanted tumors in mice. Results of human clinical trials of antivascular agents, however, have been less promising. An explanation for this diparity may be that the vasculature in most human cancers is less susceptible to therapy than the vasculature of transplanted mouse tumors usually used in preclinical studies. This is suggested by study of pericytes, which are mesenchymal cells that cover microvessels as they mature and stabilize. Pericyte coverage marks tumor vessels that appear resistant to antivascular therapy, and manipulated increases or decreases in the fraction of pericyte-covered vessels in transplanted tumors attenuate or enhance their response to the antivascular agent, rmIL-12. Significantly, pericytes cover most vessels in many human cancers but cover few vessels in transplanted mouse tumors. Autochthonous mouse mammary tumor virus (MMTV)-induced mammary carcinomas have vessels that are mostly pericyte-covered and that are refractory to rmI?-12 antivascular effects. Based on this and the hypothesis that pericyte-coverage correlates with and may be responsible for tumor vessel refractoriness to antivascular therapy, MMTV tumors and other autochthonous mammary tumors with similar vasculature are proposed as more faithful models of human tumor vasculature for evaluating antivascular therapy.
Aim 1 is to characterize the vasculature of autochthonous mammary carcinomas arising by MMTV insertional activation and transgenic expression of oncogenes and to study the tumor and vascular response of these tumors to different antivascular agents.
Aim 2 is to examine vascular development during progression and growth of MMTV mammary carcinomas and other autochthonous mammary tumors that have extensive vessel pericyte coverage to understand the basis of their vessel maturity.
Aim 3 is to test whether manipulation of Tie2 activation reduces pericyte coverage of MMTV tumor vessels and improves their response to antivascular therapy using a transgenic approach to achieve Dox-regulable, mammary expression of Tie2Ex, an inhibitor of Tie2 activation. These studies will define the importance and therapeutic implications of tumor vessel pericyte coverage and reveal the etiology of extensive pericyte coverage of tumor vessels. In addition to being relevant to understanding human cancer vasculature and clinical antivascular therapy, these studies point to the use of mouse tumors that more closely model human tumor vasculature and that may make preclinical studies of antivascular therapy more informative.
