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8  Vascular and Interstitial Biology of Tumors

Rakesh K. Jain, Vikash P. Chauhan, and Dan G. Duda

SUMMARY O F K E Y P O I N T S
• A solid tumor is an organ composed vascular permeability, blood flow, heterogeneity and directly
of neoplastic cells and stromal and the microenvironment. hinders the penetration of large-
cells nourished by a vasculature • Tumor interstitial matrix is formed of molecular-weight therapeutics.
made of endothelial cells—all proteins secreted by stromal and Alleviating interstitial hypertension
embedded in an extracellular cancer cells and by those leaked improves oxygen and drug delivery
matrix. The interactions among from the nascent blood vessels. to tumors.
these cells and between these • Tumor interstitium is heterogeneous, • Judicious application of angiogenic
cells, their surrounding matrix, with some regions fairly permeable therapy can normalize the tumor
and their local microenvironment and others difficult to penetrate. vessels and make them more
control the expression of various Modification of collagen and efficient for delivery of oxygen
genes. The products encoded by hyaluronan in the matrix can improve (a known radiosensitizer) and drugs.
these genes, in turn, control the penetration of large-molecular- Antiangiogenic agents can prune
pathophysiological characteristics weight therapeutics. tumor vessels, induce cancer cell
of the tumor. Tumor pathophysiology • Solid components of tumors—cancer apoptosis, and lower interstitial
governs not only tumor growth, cells, stromal cells, and matrix hypertension in tumors.
invasion, and metastasis but also the molecules—mechanically compress • Thus far, eight antiangiogenic agents
response to various therapies. blood and lymphatic vessels, have been approved for patients with
• Tumor vasculature is made of host resulting in reduced perfusion that certain types of cancer. Based on
vessels co-opted by cancer cells limits oxygen and drug supply. these successes, antiangiogenic
and by new vessels formed by the Depleting these constituents therapy is expected to make a
processes of vasculogenesis and decompresses blood vessels difference in many other tumor
angiogenesis. A constellation of to enhance perfusion and drug types. Two main hurdles to further
positive and negative regulators of delivery. development of antiangiogenic
angiogenesis governs the process of • Interstitial hypertension is a hallmark agents are the better understanding
neovascularization. of solid tumors and results from of the mechanisms of action of these
• Tumor vessels are abnormal in terms vessel leakiness, lack of functional agents and the development of
of their organization, structure, and lymphatics, and compression of biomarkers to select patients for
function. These abnormalities vessels. This elevated fluid pressure these drugs and to predict and
contribute to heterogeneity in contributes to blood flow monitor their effects.

INTRODUCTION VASCULAR COMPARTMENT

A solid tumor is an organ composed of neoplastic cells and host
stromal cells nourished by a vasculature made of endothelial
cells—all embedded in an extracellular matrix (Fig. 8-1). The
interactions among these cells and between these cells, their sur-
rounding matrix, and their local microenvironment control the
expression of various genes. The products encoded by these genes,
in turn, control the pathophysiological characteristics of the tumor.
Tumor pathophysiology governs not only tumor growth, invasion,
and metastasis but also the response to various therapies. In this
chapter we will discuss various pathophysiological parameters that
characterize the vascular and extravascular compartments of a tumor
and the mechanisms governing the formation and function of
these compartments.
Neoplastic cells, like normal cells, need oxygen and other nutrients
for their survival and growth. Every normal cell in our body is located
within 100 to 200  µm from a blood capillary so it can receive oxygen
and other nutrients by the process of diffusion. Likewise, cells under-
going neoplastic transformation depend on nearby capillaries for
growth. These preneoplastic (i.e., hyperplastic or dysplastic) cells can
grow as a spherical or ellipsoidal cellular aggregate. Once the size of
the cellular aggregate reaches the diffusion limit for critical nutrients
and oxygen, however, the aggregate as a whole can become dormant.
Indeed, human tumors can remain dormant for many years because
of a balance between neoplastic cell proliferation and apoptosis.
However, once they have access to new blood vessels, they may grow
and metastasize. What triggers the growth of new vessels? What

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