Abstract
The growth of a malignant tumor beyond a certain, limited size requires that it first develop an independent blood supply. In addition to providing metabolic support, this neovasculature also allows tumor cells to access the systemic circulation, thus facilitating metastatic dissemination. The neovasculature may originate either from normal blood vessels in close physical proximity to the tumor and/or from the recruitment of bone marrow-derived endothelial cell (EC) precursors. Recent studies have shown that human tumor vasculature ECs may also arise directly from tumor cells themselves and that the two populations have highly similar or identical karyotypes. We now show that, during the course of serial in vivo passage, these tumor-derived ECs (TDECs) progressively acquire more pronounced EC-like properties. These include higher-level expression of EC-specific genes and proteins, a greater capacity for EC-like behavior in vitro, and a markedly enhanced propensity to incorporate into the tumor vasculature. In addition, both vessel density and size are significantly increased in neoplasms derived from mixtures of tumor cells and serially passaged TDECs. A comparison of early- and late-passage TDECs using whole-genome single nucleotide polymorphism profiling showed the latter cells to have apparently evolved by a process of clonal expansion of a population with a distinct pattern of interstitial chromosomal gains and losses affecting a relatively small number of genes. The majority of these have established roles in vascular development, tumor suppression or epithelial-mesenchymal transition. These studies provide direct evidence that TDECs have a strong evolutionary capacity as a result of their inherent genomic instability. Consequently such cells might be capable of escaping anti-angiogenic cancer therapies by generating resistant populations.
Highlights
The growth of a tumor beyond a certain small size is highly dependent upon the development of an independent vasculature [1,2,3,4]
tumor-derived ECs (TDECs) Recovery Increases with Serial Passage The H460 human lung cancer cell line was originally tagged with lentiviral vectors separately encoding green fluorescent protein (GFP) and resistance to G418 [16]
These findings are supported by recent observations that a substantial proportion of tumor-associated ECs’’ (TAECs) from primary human glioblastomas appear to be of tumor cell or tumor stem cell origin [17,18]
Summary
The growth of a tumor beyond a certain small size is highly dependent upon the development of an independent vasculature [1,2,3,4]. The first, termed ‘‘sprouting’’ angiogenesis, or angiogenesis, is a consequence of the re-directing of pre-existing neighboring blood vessels into the tumor bed, whereas the second, termed vasculogenesis, stems from the recruitment of bone marrowderived endothelial cell (EC) precursors [7,8]. Both processes may operate independently and concurrently and are regulated by specific inductive signals originating from the tumor and/or its associated inflammatory cell infiltrate [8,9]. It serves as a major portal for tumor cell invasion of the systemic circulation, abetting metastasis [3,6]
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