Interstitial fluid pressure and capillary diameter distribution in human melanoma xenografts.

Tumors have been shown to differ substantially in interstitial fluid pressure (IFP), but the biological properties of tumors governing the intertumor heterogeneity in IFP have not been identified conclusively. The purpose of the work reported here was to investigate whether the IFP of tumors is influenced significantly by the diameter distribution of the capillaries and hence by the geometric resistance of the capillary network to blood flow. Tumors of three human melanoma xenograft lines (D-12, R-18, U-25) showing similar capillary densities were included in the study. IFP was measured using the wick-in-needle technique. Capillary diameter distribution was determined by stereological analysis of histological sections. The lines differed significantly in tumor IFP (P < 0.05) and capillary diameter distribution (P < 0.05). Mean IFP was 6 mm Hg (D-12), 17 mm Hg (R-18), and 11 mm Hg (U-25). The mean of the mean capillary diameter was 13.1 microm (D-12), 10.9 microm (R-18), and 12.0 microm (U-25). The sequence of the lines from low to high IFP was the same as the sequence of the lines from large to small mean capillary diameter: D-12, U-25, R-18. Also, individual tumors of the same line differed substantially in IFP and in mean capillary diameter. IFP ranged from 2 to 15 mm Hg (D-12), from 2 to 36 mm Hg (R-18), and from 4 to 30 mm Hg (U-25). Mean capillary diameter ranged from 11.0 to 14.6 microm (D-12), from 9.5 to 11.7 microm (R-18), and from 10.4 to 13.0 microm (U-25). Inverse linear correlations between tumor IFP and mean capillary diameter were found for each of the melanoma lines [P < 0.05, R(2) = 0.85 (D-12); P < 0.05, R(2) = 0.86 (R-18); P < 0.01, R(2) = 0.93 (U-25)]. Moreover, the IFP and mean capillary diameter of individual tumors varied with tumor size in all lines. IFP decreased during tumor growth whereas mean capillary diameter increased with increasing tumor volume (P < 0.001). Taken together, these data suggest that the diameter distribution and hence the geometric resistance of the capillary network exerts significant influence on the IFP of tumors.

[1]  R K Jain,et al.  Interstitial hypertension in carcinoma of uterine cervix in patients: possible correlation with tumor oxygenation and radiation response. , 1991, Cancer research.

[2]  R. Reed,et al.  Interstitial fluid pressure in rats measured with a modified wick technique. , 1977, Microvascular research.

[3]  R K Jain,et al.  Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. , 1988, Cancer research.

[4]  R. Jain,et al.  Interstitial fluid pressure in solid tumors following hyperthermia: possible correlation with therapeutic response. , 1992, Cancer research.

[5]  E. Rofstad,et al.  Vascular structure of the C3H mammary carcinoma, the B16 melanoma and the Lewis lung carcinoma in syngeneic, conventional mice and congenitally athymic mice. , 1985, European journal of cancer & clinical oncology.

[6]  E. Rofstad,et al.  Vascular structure of five human malignant melanomas grown in athymic nude mice. , 1982, British Journal of Cancer.

[7]  R. Jain,et al.  Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice. , 1992, Cancer research.

[8]  D. Longo,et al.  Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients: changes during treatment. , 1993, Cancer research.

[9]  R. Reed,et al.  Interstitial fluid pressure in DMBA-induced rat mammary tumours. , 1982, Scandinavian journal of clinical and laboratory investigation.

[10]  R K Jain,et al.  Tumor angiogenesis and interstitial hypertension. , 1996, Cancer research.

[11]  E. Rofstad,et al.  Interstitial fluid pressure in human melanoma xenografts. Relationship to fractional tumor water content, tumor size, and tumor volume-doubling time. , 1995, Acta oncologica.

[12]  R K Jain,et al.  Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. , 1990, Cancer research.

[13]  R K Jain,et al.  Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. , 1992, Cancer research.

[14]  R K Jain,et al.  Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure. , 1989, Cancer research.

[15]  R K Jain,et al.  Interstitial hypertension in superficial metastatic melanomas in humans. , 1991, Cancer research.

[16]  R K Jain,et al.  Determinants of tumor blood flow: a review. , 1988, Cancer research.

[17]  R. K. Jain,et al.  Interstitial fluid pressure in intracranial tumours in patients and in rodents. , 1997, British Journal of Cancer.

[18]  E. Rofstad,et al.  Step-down heating of human melanoma xenografts: effects of the tumour microenvironment. , 1994, British Journal of Cancer.

[19]  R. Jain,et al.  Nicotinamide can lower tumor interstitial fluid pressure: mechanistic and therapeutic implications. , 1992, Cancer research.

[20]  L. M. Cobb.  Intratumour factors influencing the access of antibody to tumour cells , 2004, Cancer Immunology, Immunotherapy.

[21]  H Lyng,et al.  Vascular density in human melanoma xenografts: relationship to angiogenesis, perfusion and necrosis. , 1998, Cancer letters.

[22]  E. Rofstad,et al.  Orthotopic human melanoma xenograft model systems for studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern. , 1994, British Journal of Cancer.

[23]  R. K. Jain,et al.  Reduction of interstitial fluid pressure after TNF-alpha treatment of three human melanoma xenografts. , 1996, British Journal of Cancer.

[24]  R K Jain,et al.  Transport of molecules in the tumor interstitium: a review. , 1987, Cancer research.

[25]  M. Hashida,et al.  Experimental study on lymphatic vascular changes in the development of cancer. , 1981, Lymphology.

[26]  J. Leith,et al.  Changes in the extents of viable and necrotic tissue, interstitial fluid pressure, and proliferation kinetics in clone A human colon tumour xenografts as a function of tumour size , 1994 .

[27]  P. Okunieff,et al.  Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. , 1989, Cancer research.

[28]  R. Jain,et al.  Microvascular permeability of normal and neoplastic tissues. , 1986, Microvascular research.