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• The VEGF ligand and angiogenesis
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• VEGF: The predominant mediator of angiogenesis
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• VEGF in tumor growth
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• Increase in interstitial pressure

Why is interstitial pressure important?

Interstitial pressure in tumors⁶³

With the exception of the periphery of a tumor, where interstitial pressure remains at close to normal levels, the interstitial pressure within a tumor is remarkably high. Large molecules, such as therapeutic agents, tend to travel by convection (from areas of high pressure to areas of low pressure). At areas of low interstitial pressure, such as the periphery of a tumor, agents are easily able to leave the bloodstream and enter surrounding cells because the pressure in the blood vessels is greater than the pressure in the interstitium. When interstitial pressure is higher, it may exceed pressure in the vasculature. As a consequence, convection virtually ceases, and delivery of agents from the bloodstream to tumor cells is impeded.^65-67

Jain RK. Sci Am. 1994;271:58-65.

Tumors are not composed entirely of malignant cells. In fact, less than half of a tumor's volume may be cancer cells, 1% to 10% may be blood vessels, and the remainder is interstitium, a collagen-rich matrix that surrounds cancer cells and separates them from the vasculature.^65,68

The vasculature induced by vascular endothelial growth factor (VEGF) is leaky due to gaps between endothelial cells and openings within the cells themselves.^69,70 Because of the hyperpermeable nature of VEGF-induced vasculature, fluid can leak from tumor vessels into the interstitium.^7,65 The result is remarkably high interstitial pressure throughout the interior of a tumor, while pressure in the outermost areas remains at close to normal levels.⁶⁵ By contrast, pressure in veins—the predominant vessels in tumors—is reduced in tumor veins compared with veins in normal tissue. Thus, there is a dual effect of increased interstitial pressure and decreased vascular pressure in tumors.⁶⁸

Since high molecular-weight molecules, including therapeutic agents, travel in large part by convection (from areas of high pressure to areas of low pressure), the high interstitial pressure of tumors can impede the delivery of therapeutic agents from the bloodstream to tumor cells.^65,67

High interstitial pressure has been demonstrated in a variety of tumor types, as shown below.⁶⁵

Types of Tissue	Number of Patients	Mean Pressure
Normal breast	8	0.0
Normal skin	5	0.4
Renal cell carcinoma	1	38.0
Cervical carcinoma	26	22.8
Colorectal liver metastases	8	21.0
Head and neck carcinoma	27	19.0
Breast carcinoma	8	15.0
Metastatic carcinoma	12	14.3
Lung carcinoma	26	10.0

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