Tumor Angiogenesis and Neovasculature

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. 1998581408-1416, 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. 2000575-12,
with permission.
5
Vascular Targeting AgentsGreater Effect on
Shape of Proliferating vs Confluent Endothelial
Cells
HUVEC Human umbilical vascular endothelial
cells. Modified from Galbraith et al. Anticancer
Res. 20012193-102, 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 Siemann et al, unpublished data.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. 200253164-171 and Siemann et
al. Int J Cancer. 2002991-6, with permission.
9
Vascular Targeting Agents Effect on Perfusion
of Tumor vs Normal Tissue (Murine Adenocarcinoma
Model)
(P lt .0006 vs. normal tissues)

From Chaplin et al. Anticancer Res.
199919189-196, 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.
200253164-171, 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. 200253164-171, and Siemann et
al. Int J Cancer. 2002991-6, with permission.
13
Vascular Targeting AgentInduced 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.
199919189-196, 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.
200281974-1983, 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. 2002991-6,
with permission.