Tumor vessel

A more elaborate approach was taken by Kaffy et al. [94], The goal of the research was a series of compounds with greater stability and a higher affinity for endothelial cells within tumor vessels than CA-4, 7 however, the paper described a method that was purely synthetic. The synthetic strategy involved a 1,3-dipolar cycloaddition of a nitrile oxide 186 with a substituted aryl alkyne 187 to form the oxazole 188. 

Blood vessels penetrating tumors provide malignant cells with another point at which to enter the circulation. Evidence exists that in situation where cancers disseminate predominantly by the blood, the extent of metastasis depends upon the vasculature of the primary tumor. Thin-walled capillaries, especially those newly formed, provide poor resistance to invading cancer cells. Also, data from microscopy studies show that the endothelium of tumor vessels, particularly in areas of poor oxygenation, is often abnormal (Kl). These abnormalities may permit invasion by neoplastic cells (P3). Finally, tumors can spread by direct extension into body cavities such as pleural and peritoneal spaces. An example of this is the formation of peritoneal metastases from ovarian carcinoma. 

Krasnici S, et al. Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels. Int J Cancer 105, 561, 2003 Hood J, et al. Tumor regression by targeted gene delivery to the neovasculature. Science 2002 296 2404. 

Power Doppler sonography displays the amplitude of the Doppler signal but lacks the velocity and directional information present in frequency-based color Doppler sonography (10). However, power Doppler is more sensitive in the depiction of tumor vascularity (14-16), specifically within small tumor vessels (10,17). The hind limb tumor model and power Doppler can be utilized to measure the response of tumor blood vessels to radiation, providing longitudinal assessment of microvascular response within the same tumor without the need to section tumors for histology at various time intervals. 

Hosoki T, Mitomo M, Chor S, et al. Visualization of tumor vessels in hepatocellular carcinoma power Doppler compared with color Doppler and angiography. Acta Radiol 1997 38 422-427. 

The vascular endothelial growth factor is produced by tumor cells, macrophages, and endothelial and smooth muscle cells. It induces vascular endothelial cell migration, enhances vascular permeability, and promotes extravasation of plasma proteins from tumor vessels to form an extracellular matrix, facilitating inward migration of endothelial cells (Callagy et al., 2000). These characteristics impart selectivity to VEGF for endothelial cells. 

Hobbs, S.K., Monsky, W., Yuan, F., Roberts, W.G., Griffith, L., Torchillin, V.P. et al. (1998) Regulation of transport pathways in tumor vessels Role of tumor type and microenviron-ment. Proc. Nat. Acad. Sci. USA, 95, 4607-4612. 

Bruns CJ, Koehl GE, Guba M, et al. Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer. Clin Cancer Res 2004 10(6) 2109—21 19. 

In addition to differences between tumors and their environment, the neo vascular phenotype itself may differ between tissues. A variety of vascular morphologies has been discussed above, and specific molecules expressed by the neovasculature may also vary. For example, binding of the antiangiogenic factor endostatin was found to almost all bladder tumor vessels, three quarters of the vessels in prostatic carcinomas, and only 11% of renal tumor vessels [63]. VEGFR3, which, in most tissues, is restricted to lymphatics, has been identified in the new blood vessels of inflamed synovium [26]. These and other characteristics of different neo vascular beds may contribute to heterogeneous responses to therapies that target the vasculature. 

Yonenaga Y, Mori A, Onodera H, Yasuda S, Oe H, Fujimoto A, et al. Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology 2005 69 159-166. 

Liotta, L. A., Kleinerman, J. and Saidel, G. M. (1974). Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res. 34, 997-1004. 

A permeabihzing effect on the tumor vessels leading to collapse of intratu-moral capillaries [26]. 

K. Regulation of transport pathways in tumor vessels role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA 1998, 95, 4607-4612. 

Rodas RA, Fenstermaker RA, McKeevet PE, et al. Cottelation of intraluminal thrombosis in brain tumor vessels with postopet-ative thrombotic complications. / Neurosurg. 1998 89 200-205. 

The tumor vessels may be distinguished from their normal counterparts architecturally, they are irregularly shaped, dilated, tortuous and even contain dead ends [84]. Extensive fenestration, an abnormal basement membrane and unusual wide gaps between adjacent endothelial cells make them leaky [85-87]. 

Hashizume, H., Baluk, P., Morikawa, S., McLean, J.W., Thurston, G., Roberge, S., Jain, R.R., and McDonald, D. M. (2000) Openings between defective endothelial cells explain tumor vessel leakiness, Am J Pathol 156, 1363-1380. 

In some cases, selective accumulation in the target area can be achieved, and this is of major interest in cancer therapy. For example, compared to normal tissue, tumor vessels can take up conjugates with a molecular weight >40 kDa. In addition, the lymphatic system in these areas is unable to provide a full drainage function, and this may lead to an enhanced perme-abihty and retention effect (EPR) of high-molecular weight compounds. Small molecules are not accumulated as they are able to diffuse back into the blood circulation... 

Fig. 4. Molecular-weight dependence of effective vascular permeability. Vascular permeability to 150,000 MW dextran (D150) is about one order of magnitude higher in tumor vessels than in the host tissue (data from Gerlowski and Jain, 1986). Even though albumin has a lower molecular weight ( 70,000), because of its globular configuration, it has a lower permeability than D150 (Yuan et al., 1993). Liposomes with diameters between 80 and 100 nm have even lower permeability in the tumor (Yuan et al., 1994).

Now consider a more realistic situation, where the tumor vessels are 200 /urn apart and uniformly perfused, but Pi has increased in the center so that fluid extravasation, and hence convective transport of macromolecules across vessels, has stopped. In such a case the only way macromolecules extravasate in the center is by the slow process of diffusion across vessel walls. Also, they can reach the center from the periphery (where is near zero) by interstitial diffusion. As stated earlier, if the distance between the center and periphery is — 1 mm, it would take days for them to get there, and if it is 1 cm, it would take months (Clauss and Jain, 1990). If, owing to cellular proliferation, the central vessels have collapsed completely, then there is no delivery of macromolecules by blood flow to the necrotic center (Jain, 1988 Baxter and Jain, 1990). In such a case there are no molecules available for extravasation by diffusion across the vessel wall, and consequently the central concentration would be even lower (Baxter and Jain, 1990). However, once the molecules have arrived there, the central region may serve as a reservoir for slow release later when the periphery has been cleared by plasma. 

The adhesion of these cells to the tumor vessel wall occurs when the force between the adhesion molecules on the surfaces of endothelium and effector cell is greater than the hydrodynamic force exerted by blood flow. The deformability of these cells also plays an important role in this process, since it can alter the surface area of contact (Sasaki et al., 1989 Melder and Jain, 1992). Measurement of forces exerted by various adhesion molecules as well as cell deformability in vitro and in vivo is an active area of research in many laboratories, including our own (Ohkubo et al., 1991 Munn et al., 1994). 

Interstitial fluid pressures in normal tissues are approximately atmospheric or slightly sub-atmospheric, but pressures in tumors can exceed atmospheric by 10 to 30mmHg, increasing as the tumor grows. For 1-cm radius tumors, elevated interstitial pressures create an outward fluid flow of 0.1 fim/s [11]. Tumors experience high interstitial pressures because (i) they lack functional lymphatics, so that normal mechanisms for removal of interstitial fluid are not available, (ii) tumor vessels have increased permeability, and (iii) tumor cell proliferation within a confined volume leads to vascular collapse [12]. In both tissue-isolated and subcutaneous tumors, the interstitial pressure is nearly uniform in the center of the tumor and drops sharply at the tumor periphery [13]. Experimental data agree with mathematical models of pressure distribution within tumors, and indicate that two parameters are important determinants for interstitial pressure the effective vascular pressure, (defined in Section 6.2.1), and the hydraulic conductivity ratio, (also defined in Section 6.2.1) [14]. The pressure at the center of the tumor also increases with increasing tumor mass. 

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