Heterogeneity of the Tumor Vasculature

Abstract

The blood vessels supplying tumors are strikingly heterogeneous and differ from their normal counterparts with respect to organization, structure, and function. Six distinctly different tumor vessel types have been identified, and much has been learned about the steps and mechanisms by which they form. Four of the six vessel types (mother vessels, capillaries, glomeruloid microvascular proliferations, and vascular malformations) develop from preexisting normal venules and capillaries by angiogenesis. The two remaining vessel types (feeder arteries and draining veins) develop from arterio-venogenesis, a parallel, poorly understood process that involves the remodeling of preexisting arteries and veins. All six of these tumor vessel types can be induced to form sequentially in normal mouse tissues by an adenoviral vector expressing vascular endothelial growth factor (VEGF)-A164. Current antiangiogenic cancer therapies directed at VEGF-A or its receptors have been of only limited benefit to cancer patients, perhaps because they target only the endothelial cells of the tumor blood vessel subset that requires exogenous VEGF-A for maintenance. A goal of future work is to identify therapeutic targets on tumor blood vessel endothelial cells that have lost this requirement.

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…Both human and mouse tumors show considerable variation in the density, morphology and functionality of blood vessels (Langenkamp and Molema, 2009; Nagy et al., 2010). Furthermore, the endothelial cells of tumor blood vessels can display features –fenestration patterns, pericyte and inflammatory‐cell association, proliferation and apoptosis rates, and gene expression profiles – that vary not only among different tumor types or individual tumors, but also in a local–regional manner within a given tumor.…”

“…Furthermore, the endothelial cells of tumor blood vessels can display features –fenestration patterns, pericyte and inflammatory‐cell association, proliferation and apoptosis rates, and gene expression profiles – that vary not only among different tumor types or individual tumors, but also in a local–regional manner within a given tumor. Such heterogeneity may be influenced by the site in which a tumor arises (i.e., the specific organ or tissue microenvironment), the tumor growth stage, the biophysical properties of the surrounding stroma (e.g., interstitial pressure, collagen cross‐linking and extra‐cellular matrix tension), and many other ill‐defined spatiotemporal differences such as angiogenic gene expression by tumor and stromal cells (Carmeliet and Jain, 2011a; Chung and Ferrara, 2011; Hanahan and Weinberg, 2011; Kerbel, 2008; Leite de Oliveira et al., 2011; McDonald and Choyke, 2003; Nagy et al., 2010; Potente et al., 2011; Weis and Cheresh, 2011). As a consequence of these many variables affecting vascular phenotypes, experimental tumors growing subcutaneously in mice may differ significantly from spontaneous tumors in terms of vascular density, functionality, phenotype, and gene expression.…”

“…Although human tumors display type‐specific vascular patterns, our understanding of such variability is mostly limited to histo‐pathological features (Langenkamp and Molema, 2009; Nagy et al., 2010). Different human cancers are variably sensitive to antiangiogenic drugs (e.g., inhibitors of endothelial TK receptors or antibodies that block vascular growth factors); furthermore, tumors of a generally refractory type may sporadically show dramatic responses to antiangiogenic drugs (Carmeliet and Jain, 2011b; Chung et al., 2010; Goel et al., 2011; Leite de Oliveira et al., 2011).…”

Assessement of angiogenesis reveals blood vessel heterogeneity in lung carcinoma

“…A total of six tumor vessel types have been identified. Four vessel types (mother vessels, capillaries, glomeruloid microvascular proliferations and vascular malformations) develop from preexisting normal venules and capillaries, and two vessel types (feeder arteries and draining veins) develop from arterio-venogenesis, a parallel process that involves the remodeling of preexisting arteries and veins (5). There are several well-known mechanisms of blood vessel formation in normal and tumor tissues, including sprouting angiogenesis, vasculogenesis, intussusception, vessel co-option, vasculogenic mimicry and tumor cell-endothelial cell transdifferentiation (6).…”

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters

“…Since neoangiogenesis was identified as a fundamental factor in tumor growth, many antiangiogenic agents have been developed 1, 2, 3, 4, 5, 6. Despite an early expectation that these therapeutic agents would successfully increase survival time in patients with solid tumors, validation of meaningful survival benefits has failed in a considerable number of clinical trials.…”