Why Normalize the Tumor Vasculature

As described in Section 3.1, tumor vasculature is structurally and functionally abnormal. Blood vessels are leaky, tortuous, dilated, and saccular and have a haphazard pattern of interconnection (Figure 3.9). The endothelial cells lining these vessels have aberrant morphology; pericytes (cells that provide support for the endothelial cells) are loosely attached or absent; and the basement membrane is often abnormal—unusually thick at times, entirely absent at others. These structural abnormalities contribute to spatial and

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FIGURE 3.9 (See color insert following page 558.) Proposed role of vessel normalization in the response of tumors to antiangiogenic therapy. (a) Tumor vasculature is structurally and functionally abnormal. It is proposed that antiangiogenic therapies initially improve both the structure and the function of tumor vessels. However, sustained or aggressive antiangiogenic regimens may eventually prune away these vessels, resulting in a vasculature that is both resistant to further treatment and inadequate for the delivery of drugs or oxygen. (b) Dynamics of vascular normalization induced by VEGFR-2 blockade. On the left is a two-photon image showing normal blood vessels in skeletal muscle; subsequent images show human colon carcinoma vasculature in mice at day 0, day 3, and day 5 after administration of VEGR2-specific antibody. (c) Diagram depicting the concomitant changes in pericyte and basement membrane coverage during vascular normalization. (d) These phenotypic changes in the vasculature may reflect changes in the balance of pro- and antiangiogenic factors in the tissue. (Reproduced from Jain, R.K., Science, 307, 58, 2005. With permission.)

FIGURE 3.9 (See color insert following page 558.) Proposed role of vessel normalization in the response of tumors to antiangiogenic therapy. (a) Tumor vasculature is structurally and functionally abnormal. It is proposed that antiangiogenic therapies initially improve both the structure and the function of tumor vessels. However, sustained or aggressive antiangiogenic regimens may eventually prune away these vessels, resulting in a vasculature that is both resistant to further treatment and inadequate for the delivery of drugs or oxygen. (b) Dynamics of vascular normalization induced by VEGFR-2 blockade. On the left is a two-photon image showing normal blood vessels in skeletal muscle; subsequent images show human colon carcinoma vasculature in mice at day 0, day 3, and day 5 after administration of VEGR2-specific antibody. (c) Diagram depicting the concomitant changes in pericyte and basement membrane coverage during vascular normalization. (d) These phenotypic changes in the vasculature may reflect changes in the balance of pro- and antiangiogenic factors in the tissue. (Reproduced from Jain, R.K., Science, 307, 58, 2005. With permission.)

temporal heterogeneity in tumor blood flow. In addition, solid pressure generated by proliferating cancer cells compresses intratumor blood and lymphatic vessels, which further impairs not only the blood flow but also the lymphatic flow [29]. Collectively, these vascular abnormalities lead to an abnormal tumor microenvironment characterized by interstitial hypertension (elevated hydrostatic pressure outside the blood vessels), hypoxia, and acidosis. Impaired blood supply and interstitial hypertension interfere with the delivery of therapeutics to solid tumors. Hypoxia renders tumor cells resistant to both radiation and several cytotoxic drugs. Independent of these effects, hypoxia also induces genetic instability and selects for more malignant cells with increased metastatic potential [30]. Hypoxia and low pH also compromise the cytotoxic functions of immune cells that infiltrate a tumor. Unfortunately, cancer cells are able to survive in this abnormal microenvironment. In essence, the abnormal vasculature of tumors and the resulting abnormal microenvironment together pose a formidable barrier to the delivery and efficacy of cancer therapy. This suggests that if we knew how to correct the structure and function of tumor vessels, we would have a chance to normalize the tumor microenvironment and ultimately to improve cancer treatment. The fortified tumor vasculature may also inhibit the shedding of cancer cells into the circulation—a prerequisite for metastasis. In the past, higher doses of drugs and hyperbaric oxygenation have been used to increase the tumor concentrations of drugs and oxygen, respectively. These strategies have not shown much success in the clinic, however. One reason for this failure is that tumor vessels have large holes in their walls [129]. As stated earlier, this leakiness leads to interstitial hypertension as well as spatially and temporally nonuniform blood flow. If the delivery system is flawed, it does not matter how much material is pumped into it. The drugs and oxygen become concentrated in regions which already have enough and still not reach the inaccessible regions [130]. However, if we fix the delivery system, more cells are likely to encounter an effective concentration of drugs and oxygen. This is the rationale for developing therapies that normalize the tumor vasculature. These therapies do not merely increase the total uptake of drugs and oxygen but also distribute these molecules to a larger fraction of the tumor cells by fixing the delivery system.

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