The proliferation of neoplastic cells in a confined space collapses blood vessels thus restricting the penetration and uniform distribution of therapeutic agents in tumors. Our recent data also shows that growth of tumor spheroids in a confined space can upregulate the expression of hyaluronan an interstitial matrix (IM) molecule that hinders interstitial fluid movement and molecular diffusion. The induction of apoptosis by taxol alleviates the confined space effects, thus improving vascular perfusion and fluid flow through the tumor IM. In contrast, radiation reduces fluid flow through the tumor IM. Thus the objectives of the proposed study will be to determine: 1) the effects of taxol and radiation on interstitial transport, and on the production of IM molecules, 2) test the hypothesis that growth in a confined space upregulates the expression of glycosaminoglycans by tumor cells and reduces diffusive transport and 3) determine if the void spaces induced by apoptosis produce interstitial pathways that favor a rapid and more uniform penetration of viruses. Fluorescence recovery after photobleaching and measurements of hydraulic conductivity will test the hypothesis that taxol enhances interstitial transport in tumors. The transport data will be related to the levels of IM matrix molecules and apoptosis. The effects of growth in a confined space on the expression of hyaluronan will be tested in vitro by growing tumor spheroids in increasing concentrations of collagen or agarose gels. To test the hypothesis that apoptosis enhances the distribution volume of viral particles and gene transfection in tumors, apoptosis will be induced with taxol and in cells transfected with a caspase-8 inducible promoter. Multiphoton laser-scanning microscopy will be used to measure in tumors the distribution volume of viral vectors and determine if the void spaces induced by apoptosis form interconnected interstitial pathways that enhance the movement of viral particles. Sense constructs of hyaluronan synthase 2 will test the hypothesis that hyaluronan participates in the remodeling and obstruction of the void spaces following apoptotic death, thus reducing interstitial transport and the movement of viral vectors. The hypothesis that taxol-induced apoptosis (void space formation) enhances the antitumor efficacy of gene therapy will be tested. The results will provide insight on how to best combine viral vectors and cytotoxic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098706-02
Application #
6768821
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Stone, Helen B
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$283,527
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Stylianopoulos, Triantafyllos; Munn, Lance L; Jain, Rakesh K (2018) Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside. Trends Cancer 4:292-319
Daubriac, Julien; Han, Shiwei; Grahovac, Jelena et al. (2018) The crosstalk between breast carcinoma-associated fibroblasts and cancer cells promotes RhoA-dependent invasion via IGF-1 and PAI-1. Oncotarget 9:10375-10387
Mpekris, Fotios; Baish, James W; Stylianopoulos, Triantafyllos et al. (2017) Role of vascular normalization in benefit from metronomic chemotherapy. Proc Natl Acad Sci U S A 114:1994-1999
Mitchell, Michael J; Jain, Rakesh K; Langer, Robert (2017) Engineering and physical sciences in oncology: challenges and opportunities. Nat Rev Cancer 17:659-675
Kumar, Vidhya; Boucher, Yves; Liu, Hao et al. (2016) Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma. Transl Oncol 9:431-437
Rahbari, Nuh N; Kedrin, Dmitriy; Incio, Joao et al. (2016) Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci Transl Med 8:360ra135
Martin, John D; Fukumura, Dai; Duda, Dan G et al. (2016) Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity. Cold Spring Harb Perspect Med 6:
Stylianopoulos, Triantafyllos; Jain, Rakesh K (2015) Design considerations for nanotherapeutics in oncology. Nanomedicine 11:1893-907
Tolaney, Sara M; Boucher, Yves; Duda, Dan G et al. (2015) Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients. Proc Natl Acad Sci U S A 112:14325-30
Stylianopoulos, Triantafyllos; Economides, Eva-Athena; Baish, James W et al. (2015) Towards Optimal Design of Cancer Nanomedicines: Multi-stage Nanoparticles for the Treatment of Solid Tumors. Ann Biomed Eng 43:2291-300

Showing the most recent 10 out of 25 publications