The goals of this project are to characterize transport in the interstitium and relate it to the interstitial structure, to determine the etiology of interstitial hypertension, to develop strategies to alter pressure in solid tumors, and to examine the diagnostic and prognostic value of tumor interstitial pressure in the management of cancer. Since lack of functioning lymphatics is a major cause of interstitial hypertension, a related goal is to quantify lymph transport, and to identify inhibitors of lymphangiogenesis and lymphatic function in tumors.
Provided the first measurements of interstitial hypertension in various human tumors (Boucher et al., 1991, Roh et al., 1991, Gutmann et al., 1992, Less et al., 1992, Jain, 1994c, Boucher et al., 1997). Provided evidence that microvascular pressure is the principal driving force for interstitial hypertension in tumors (Boucher et al., 1992, Zlotecki et al., 1993, 1995), and that interstitial pressure goes up with the onset of angiogenesis (Boucher et al., 1996). Theoretically predicted and experimentally confirmed the time constants of transvascular and interstitial fluid exchange in tumors (Netti et al., 1995) and developed a novel strategy for improving drug delivery based on these findings (Netti et al., 1999).
Measured the hydraulic conductivity of the tumor interstitial matrix (Boucher et al., 1998). Discovered that collagen network contributes to resistance (Netti et al., 2000; Davies et al., 2002; Ramanujan et al., 2002), and to host-organ dependence of interstitial transport in tumors (Pluen, et al, 2001).
Developed a two-photon correlation microscopy technique and found two-phase nature of interstitial transport in tumors (Alexandrakis et al., 2004).
Demonstrated that VEGF signaling blockade reduces the tumor interstitial fluid pressure in experimental tumors and in human rectal cancer (Lee et al., 2000; Tong et al., 2004; Willett et al., 2004; 2005).
Developed a poro-elastic model for interstitial lymphatic transport (Swartz et al., 1999a). |
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Solid stress is transmitted through the structural elements of the interstitium and the cells. It is independent of hydrostatic pressure, which is transmitted through intra- and extracellular fluids. Cell proliferation in a confined space creates solid stress, which exerts forces on these structural elements, affecting the cells themselves as well as blood vessels. Recent reports show that gene expression in developing embryos is affected by applied mechanical stress. Mechanical stress also leads to phenotypic changes in adult cells, including cancer cells. In this project, we investigate the factors that contribute to solid stress in tumors, determine the effects of solid stress on tumor physiology, gene expression in cancer and stromal cells, and evaluate whether increased solid stress promotes metastasis. |
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Measurement of Tumor-Induced Solid Stress in Agarose Gels |
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It has been shown in our lab that solid stress from the surrounding matrix inhibits the growth of tumor spheroids in vitro [1] and that the stress may induce the expression of hyaluronan which facilitates cell-cell adhesion [2]. It was assumed that the plateau phase in spheroid size observed in those studies was due to the counterforce from the increasingly compressed agarose gels. Yet it is not clear if that is true and, if it is, how the solid stress transduces in the agarose gels. Another related question is how the stress distributes inside the spheroids. The goal of this project is to find quantitative answers to these questions. |
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Interstitial Fluid Pressure |
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Model Summary Jain et al. Cancer Research 2007; 67:2729-2735
Preclinical and clinical evidence shows that anti-angiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel “normalization.” The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and IFV (interstitial fluid velocity) are affected by changes in transport properties of the vessels and interstitium that are associated with anti-angiogenic therapy. |
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Interstitium: Oncolytic Virus |
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The therapeutic success of oncolytic viruses and other large anti-cancer agents is severely limited by their poor diffusion and distribution through the tumor interstitial space. We have shown that collagen fibers in the tumor interstitial matrix hinder the diffusion of large molecules and penetration of viral particles. We used relaxin - a small hormone - which stimulates the secretion of matrix metalloproteinases and inhibits collagen synthesis - to improve the diffusion of large molecules in collagen-rich tumors. |
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