Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%–60% of tumor vasculature. Empty sleeves of basement membrane were left behind. Pericytes also survived but had less α–SMA immunoreactivity. One day after drug withdrawal, endothelial sprouts grew into empty sleeves of basement membrane. Vessel patency and connection to the bloodstream followed close behind. By 7 days, tumors were fully revascularized, and the pericyte phenotype returned to baseline. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first. Inhibition of MMPs or targeting of type IV collagen cryptic sites by antibody HUIV26 did not eliminate the sleeves or slow revascularization. These results suggest that empty sleeves of basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGF therapy and highlight their importance as potential targets in cancer therapy.
Michael R. Mancuso, Rachel Davis, Scott M. Norberg, Shaun O’Brien, Barbara Sennino, Tsutomu Nakahara, Virginia J. Yao, Tetsuichiro Inai, Peter Brooks, Bruce Freimark, David R. Shalinsky, Dana D. Hu-Lowe, Donald M. McDonald
Submitter: Enrique Casado | email@example.com
Unidad de Oncología Traslacional. Hospital Universitario La Paz, Madrid, Spain.
Published December 13, 2006
With regard to the article by Mancuso et al. concerning the rapid effect of vascular regrowth in tumors after reversal of VEGF inhibition, some considerations can be made with potential clinical interest. Clinical disease progression upon chemotherapy treatment defines, in clinical practice, the moment when this treatment has to be interrupted and other options considered. However, the incorporation of new targeted drugs, like bevacizumab (BVZ), to chemotherapy combinations urges to revisit this practice, as chemotherapy resistance does not necessarily entail a lack of activity, for example, in the vascular compartment.
Recently, data from a second randomized trial (1) has also shown improved disease-free survival in advanced colorectal cancer when combining BVZ with chemotherapy. However, the benefit was larger in the former trial (2) using a suboptimal chemotherapy regimen, in which, interestingly, BVZ was kept on treatment in many patients after clinical progression. Taking together this observation with the results of Mancuso et al, and pending clinical trials that specifically address this issue, it is tantalizing to maintain VEGF inhibition with following second line therapies. Of course, it is of utmost importance to validate surrogate markers, in patients, that clarify the moment when VEGF resistance develops and the escape pathway involved. Other appealing result in this paper is the potential role of residual sleeves of basement membranes and persisting pericytes in vascular regrowth. Novel combinations of BVZ with PDGFR inhibitors, like imatinib or other multitargeted tyrosin-kinase inhibitors could effectively inhibit VEGF and eliminate the scaffold provided by pericytes. But an issue that should be considered in this matter is how these combinations could affect drug delivery. VEGF inhibition normalizes blood vessels and increases chemotherapy delivery. With an apparently opposite effect, imatinib, that targets PDGFRB and disrupts pericytes, has also shown to decrease interstitial pressure (3). How these combinations can alter drug delivery is a question that has to be investigated, including which drugs, tumors, combinations and sequences are more suitable.
1. Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang T, Saltz L. First efficacy and safety results from XELOX-1/NO16966, a randomised 2x2 factorial phase III trial of XELOX vs. FOLFOX4 + bevacizumab or placebo in first-line metastatic colorectal cancer. 2006. Ann. of Oncol. 17: LBA3 (Abstr.).
2. Hurwitz H , Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, et al 2004. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 350:2335-42.
3. Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. 2001. Cancer Res 61:2929-34.