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Tumor Angiogenesis and Neovasculature

Tumor Angiogenesis and Neovasculature.

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Tumor Angiogenesis and Neovasculature

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  1. Tumor Angiogenesis and Neovasculature A, Tumors less than 1 mm3 receive oxygen and nutrients by diffusion from host vasculature. B, Larger tumors require new vessel network. Tumor secretes angiogenic factors that stimulate migration, proliferation, and neovessel formation by endothelial cells in adjacent established vessels. C, Newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth.

  2. Tumor Neovasculature: Comparative Tortuosity and Disorganization Normal colorectal mucosa Nearby colorectal cancer From Konerding et al. In Molls and Vaupel, eds. Blood Perfusion and Microenvironment of Human Tumors, 2002, with permission.

  3. Abnormal Structural Features of Tumor Microvasculature AV = arteriovenous. From Brown and Giaccia. Cancer Res. 1998;58:1408-1416, with permission.

  4. Approaches to Compromising Tumor Neovasculature A, Matrix breakdown inhibition; B, signal transduction inhibition; C, receptor antagonism; D, inhibition of endothelial cell function (eg, proliferation, migration, and tube formation); E, blockade of activators of angiogenesis; F, compromise existing tumor vasculature. From Siemann et al. Radiother Oncol. 2000;57:5-12, with permission.

  5. Vascular Targeting Agents:Greater Effect on Shape of Proliferating vs Confluent Endothelial Cells HUVEC = Human umbilical vascular endothelial cells. Modified from Galbraith et al. Anticancer Res. 2001;21:93-102, with permission.

  6. Vascular Targeting Agents: Preferential Induction of Detachment in Proliferating vs Confluent Endothelial Cells HMVEC-L = human lung microvascular endothelial cells. Siemann et al, unpublished data.

  7. Tubulin-Binding Agents: Proposed Effects on Endothelial Cells, Blood Flow, and Surrounding Tumor Vascular endothelial cells A, Tumor cells (blue) supplied with oxygen and nutrients by neovessel. B, Tubulin-binding agent entering proliferating endothelial cells and initiating depolymerization of tubulin cytoskeleton. Endothelial cells round and detach, initiating a reduction in blood flow. Tumor cells furthest from the neovessel start to undergo hypoxia (purple). C, Collapse of tubulin cytoskeleton and endothelial cell detachment and death. Tumor becomes increasingly hypoxic. D, Loss of blood vessel patency, causing tumor cell necrosis.

  8. Effect of 3 Vascular Targeting Agents on Patent Blood Vessel Number in MurineKHT Sarcoma Model Modified from Siemann and Rojiani. Int J Radiat Oncol Biol Phys. 2002;53:164-171 and Siemann et al. Int J Cancer. 2002;99:1-6, with permission.

  9. Vascular Targeting Agents: Effect on Perfusion of Tumor vs Normal Tissue (Murine Adenocarcinoma Model) (P < .0006 vs. normal tissues) * From Chaplin et al. Anticancer Res. 1999;19:189-196, with permission.

  10. Vascular Targeting Agents Induce Tumor Necrosis A, Hematoxylin and eosin staining of tumor slice from KHT sarcoma treated with saline shows very little tumor cell necrosis. B, 24 h after treatment with ZD6126 (150 mg/kg), extensive necrosis is seen in tumor core, with viable cells only at periphery (arrows). C and D, Effects seen at higher magnifications. Modified from Siemann and Rojiani. Int J Radiat Oncol Biol Phys. 2002;53:164-171, with permission.

  11. Vascular Targeting Agents: Proposed Mechanism of Antitumor Activity A, Tumor is supported by both host and new tumor vasculature. B, Tumor neovessel, but not host vessel, is compromised by the vascular targeting agent; furthermost tumor cells supplied by the tumor neovessel become hypoxic, cells at tumor edge supplied by the host vessel remain viable. C, Tumor cells supplied only by the tumor neovessel undergo hypoxic stress. D, All tumor cells supported by tumor neovessel undergo necrosis. Cells supplied by host vasculature are relatively unaffected.

  12. Vascular Targeting Agents: Effect on Tumor Survival (Murine Model) Note: A steep dose- response curve can be seen with DMXAA in relation to the antitubulin agents CA4DP and ZD6126. Modified from Siemann and Rojiani. Int J Radiat Oncol Biol Phys. 2002;53:164-171, and Siemann et al. Int J Cancer. 2002;99:1-6, with permission.

  13. Vascular Targeting Agent–Induced Cell Death: Dependence on Tumor Size Note: An inverse log-linear relationship between tumor mass and the fraction of surviving cells can be seen.  From Siemann and LoRusso. Vascular Targeting: An Emerging Approach in Cancer Therapy. Meniscus Limited. 2002.

  14. Vascular Targeting Agents and Radiotherapy: Growth Delays Note: Increased growth delays can be seen with the CA4DP/radiation combination in relation to either treatment alone. Modified from Chaplin et al. Anticancer Res. 1999;19:189-196, with permission.

  15. Vascular Targeting Agents and Chemotherapy: Growth Delays Note: Increased growth delays can be seen with the ZD6126/cisplatin combination in relation to either treatment alone. From Blakey et al. Clin Cancer Res. 2002;8:1974-1983, with permission.

  16. Vascular Targeting Agents and Chemotherapy: Cell Survival Note: Treatment with vascular targeting agents enhances the effect of chemotherapy in cisplatin-resistant (OW-1) and -sensitive (SKBR3) cells. From Siemann et al. Int J Cancer. 2002;99:1-6, with permission.

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