Abstract
PurposeInterstitial fluid pressure (IFP) is highly elevated in many solid tumors. High IFP has been associated with low radiocurability and high metastatic frequency in human melanoma xenografts and with poor survival after radiation therapy in cervical cancer patients. Abnormalities in tumor vascular networks have been identified as an important cause of elevated tumor IFP. The aim of this study was to investigate the relationship between tumor IFP and the functional and morphological properties of tumor vascular networks.Materials and MethodsA-07-GFP and R-18-GFP human melanomas growing in dorsal window chambers in BALB/c nu/nu mice were used as preclinical tumor models. Functional and morphological parameters of the vascular network were assessed from first-pass imaging movies and vascular maps recorded after intravenous bolus injection of 155-kDa tetramethylrhodamine isothiocyanate-labeled dextran. IFP was measured in the center of the tumors using a Millar catheter. Angiogenic profiles of A-07-GFP and R-18-GFP cells were obtained with a quantitative PCR array.ResultsHigh IFP was associated with low growth rate and low vascular density in A-07-GFP tumors, and with high growth rate and high vascular density in R-18-GFP tumors. A-07-GFP tumors showed chaotic and highly disorganized vascular networks, while R-18-GFP tumors showed more organized vascular networks with supplying arterioles in the tumor center and draining venules in the tumor periphery. Furthermore, A-07-GFP and R-18-GFP cells differed substantially in angiogenic profiles. A-07-GFP tumors with high IFP showed high geometric resistance to blood flow due to high vessel tortuosity. R-18-GFP tumors with high IFP showed high geometric resistance to blood flow due to a large number of narrow tumor capillaries.ConclusionsHigh IFP in A-07-GFP and R-18-GFP human melanoma xenografts was primarily a consequence of high blood flow resistance caused by tumor-line specific vascular abnormalities.
Highlights
While the interstitial fluid pressure (IFP) in normal tissues is actively controlled and remains close to atmospheric levels, IFP in most human tumors is highly elevated [1]
High IFP was associated with low growth rate and low vascular density in A-07-green fluorescent protein (GFP) tumors, and with high growth rate and high vascular density in R-18-GFP tumors
High IFP in A-07-GFP and R-18-GFP human melanoma xenografts was primarily a consequence of high blood flow resistance caused by tumor-line specific vascular abnormalities
Summary
While the interstitial fluid pressure (IFP) in normal tissues is actively controlled and remains close to atmospheric levels, IFP in most human tumors is highly elevated [1]. Theoretical and experimental studies have identified elevated IFP as an important barrier to drug delivery and, the delivery of monoclonal antibodies and other macromolecular drugs that depend on transport by convection rather than diffusion [6,7,8]. High IFP in the primary tumor has been shown to predict poor survival after radiation therapy in cervical cancer patients independent of tumor oxygenation and other prognostic factors [9,10]. Preclinical studies of human melanoma xenografts in our lab have shown an association between high IFP and low radiocurability through both hypoxia-dependent and hypoxia-independent mechanisms [11,12]. High IFP was associated with high incidence of pulmonary and lymph node metastasis in small tumors without hypoxic regions [13]
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