Interstitium

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).