Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions.

The objective of this work was to introduce a tumor vessel classification scheme and to provide the first quantitative measurements of vessel branching patterns and the related vascular dimensions in a mammary carcinoma. Mammary adenocarcinoma R3230AC tumors, grown in the rat ovarian tissue-isolated tumor preparation, were infused with Batson's No. 17 polymer and maintained at an intravascular pressure of 50 mm Hg during polymerization. Maceration of the tumor in KOH allowed visualization of the vasculature. The vessel branching patterns, lengths, and diameters were measured in four tumors (4-5 g). A centrifugal ordering scheme was devised specifically to account for the unique features of tumor microvascular network topology. The arterial networks revealed two types of branching patterns. One type of arteriolar network exhibited decreasing vessel diameters and lengths with increasing branch order. In a second type of network, the diameter and length of the vessels displayed fluctuations in both variables at higher generations. Avascular and poorly vascularized regions with sparse capillary supply were present in the tumors, but analysis of several capillary networks in vascularized regions revealed a nonplanar meshwork of interconnected vessels. The meshworks were composed of vessels with a mean segment length of 67 microns, a mean diameter of 10 microns, and a mean intercapillary distance of 49 microns. Capillary path lengths ranged from 0.5 to 1.5 mm. Thus, tumor capillary diameter was greater than that in most normal tissues and, in the regions where capillary networks existed, intercapillary spacing was in the normal range. In the venous network, diameters decreased from 650 to 20 microns for the first to ninth order venules. Venule length decreased from 5 to 0.5 mm for first to fourth order but was fairly uniform (less than 500 microns) for higher orders. In conclusion, solid tumor vascular architecture, while exhibiting several features that are similar to those observed in normal tissues, has others that are not commonly seen in normal tissues. These features of the tumor microcirculation may lead to heterogeneous local hematocrits, oxygen tensions, and drug concentrations, thus reducing the efficacy of present day cancer therapies.

Interstitial hypertension in human breast and colorectal tumors.

The efficacy of present day antineoplastic regimens depends upon the delivery and penetration of therapeutic agents through the tumor vascular and interstitial spaces to the tumor cell target. The distribution of relevant molecules or cells in a solid tumor is often poor and heterogeneous and is believed to be due to a number of pathophysiological factors, including elevated interstitial fluid pressure (IFP). Using the wick-in-needle technique, IFP was measured in primary breast and colorectal carcinomas as well as their respective metastases to the lymph nodes and liver in a total of 17 patients. IFP was also measured in one recurrent renal cell carcinoma, one melanoma metastasis to the lymph nodes, and another melanoma metastasis to the lung. IFP varied from 4 to 50 mm Hg with a mean +/- SD of 20 +/- 13 mm Hg in the neoplasms (n = 41 measurements; n = 21 tumors), while IFP in normal tissues had a mean of 2 +/- 4 mm Hg (n = 11). The mean IFPs for metastatic melanoma, primary breast carcinoma, and liver metastases from a colorectal primary were found to be 33 +/- 14, 15 +/- 9, and 21 +/- 12 mm Hg, respectively. In the renal cell carcinoma, the pressure was 38 mm Hg. These results agree with the findings of our 3 previous studies examining IFP in human superficial melanomas (14.3 +/- 12.5 mm Hg, n = 12), cervical carcinomas (15.7 +/- 5.7 mm Hg, n = 12), and head and neck tumors (13.2 +/- 8.8 mm Hg, n = 19), and indicate that in all types of human tumors studied to date, IFP was significantly elevated above that of normal tissue. This observation may be useful in localizing tumors during needle biopsy.

Geometric resistance and microvascular network architecture of human colorectal carcinoma.

OBJECTIVE: To measure the geometric resistance to blood flow in human colorectal carcinoma. Although tumor blood flow is of central importance in both the detection and the treatment of cancer, the determinants of blood flow through the neoplastic circulation are poorly understood. METHODS: Human colorectal carcinomas (tissue weight = 272 g +/- 43 g (SD), n = 6) were perfused ex vivo with a buffered physiological salt solution of known viscosity at flow rates ranging from 2.5 to 40 ml/min and perfusion pressures from 8 to 100 mm Hg. The geometric resistance was determined from the slope of the pressure-flow curve. For examination of the principal determinant of geometric resistance, the vascular architecture, one of the tumors was perfused with Batson's No. 17 polymer and macerated in KOH to produce a positive vascular east that was used for measurement of vascular branching patterns and dimensions. RESULTS: The pressure-flow relationship was linear at perfusion pressures above 40 mm Hg, and the geometric resistance, zzero, was constant at approximately 6.5 x 10(9) g/cm3. Below 40 mm Hg, zzero increased rapidly. The architecture of the arteriolar and capillary networks of human colorectal carcinoma is similar to those of experimental rodent tumors. Capillaries in planar and nonplanar meshworks had mean segment diameters of 11 +/- 2 and 9.6 +/- 2 microns, lengths of 46 +/- 24 and 107 +/- 40 microns, and intercapillary distances of 46 +/- 13 and 74 +/- 24 microns, respectively. CONCLUSIONS: The geometric flow resistance in neoplastic tissue is 1-2 orders of magnitude higher than that observed in normal tissues. A decrease in functional vascular cross-sectional area may explain the additional increase in resistance at small perfusion pressures. The observed flow resistance may be due to the specialized arteriolar and capillary network architecture, pressure exerted by proliferating cancer cells, and/or coupling between vascular and extravascular flow. These observations demonstrate that tumor vascularity alone may not be indicative of flow resistance or tumor susceptibility to blood-borne therapeutic agents.