Endothelial Cell Heterogeneity

Targeting the Tumor Vasculature

Robert R. Langley

Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

The growth and dissemination of malignant tumors are dependent on a blood supply. In response to increasing metabolic pressures, tumors enhance their vascular supply by inducing resident endothelial cells to form new vascular networks (angiogenesis), by mobilizing populations of endothelial precursor cells to the tumor site (vasculogene-sis), or by modifying the structural architecture of preexisting blood vessels (vascular remodeling). Understanding the molecular mechanisms that regulate these complex processes in different organs is essential for developing antivascular therapy.

Introduction

In his 1945 report examining the vascular response to tumor implantation, Algire concluded "an outstanding characteristic of the tumor cell is its capacity to elicit continuously the growth of new capillary endothelium from the host" [1]. Some 25 years later, enough supportive evidence had accumulated to advance the hypothesis that the progressive growth of tumors is, indeed, dependent upon the induction of angiogenesis. Since that time, considerable effort has been extended toward defining the molecular mechanisms that regulate tumor neovascularization and characterizing the phenotype of tumor blood vessels. Targeting of tumor-associated endothelium is an attractive approach to control tumor growth in that the endothelial component of the tumor is considered to be genetically stable and, therefore, not prone to develop resistance to therapy. Moreover, the tumor endothelium provides an accessible target as compared to malignant cell populations embedded within the underlying tissue parenchyma. However, although a number of angiogenic inhibitors have advanced from the laboratory into the clinical setting, their success in the patient population has, to date, been less than remarkable. One potential explanation for the limited therapeutic response is that an extensive body of evidence clearly indicates that the microcirculation of different tissues exhibits diversity at the structural, molecular, and functional levels. Determining which angiogenic factors are specific for the vessels associated with a given tumor is central for designing appropriate therapeutic regimes.

Emerging evidence indicates that hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs) that originate from either the bone marrow or other tissues may contribute to the neovascularization of tumors. HSCs and EPCs have also been found in newly developed blood vessels associated with wound healing, limb ischemia, atherosclerosis, and post-myocardial infarction. Preliminary experimental studies indicate that the homing properties of precursor cells may be exploited to produce therapy of tumors. Considerable effort is now directed toward determining the factors that mobilize and direct these cells to sites of neovascularization.

The extent to which tumors are dependent on the process of angiogenesis varies among different types of tumors. Some neoplasms, such as certain nonsmall-cell lung tumors, have been shown to meet their metabolic requirements by proliferating along the surface of preexisting blood vessels and, thus, are independent of angiogene-sis. Therefore, this form of tumor growth could be impervious to pharmacologic interventions that are directed against dividing endothelial cell populations. Perhaps a more effective approach for the management of this type of tumor growth would be to deliver therapy in a regional manner by targeting tissue-specific receptors that are present on the vascular endothelium and, thereby, alleviate much of the systemic toxicity associated with chemotherapy.

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