Cells cannot survive if they lack adequate oxygen and nutrient supply or cannot dispose of toxic molecules. Oxygen can diffuse from capillaries for only 150–200 μm. When distances of cells from a blood supply exceed this, cell death follows (1, 2). Thus, the growth and survival of tumor masses beyond 0.5 mm in diameter require neovascularization, ie, angiogenesis (3). In this issue of the Journal, Achilles et al.(4) injected human liposarcoma cells (tumor fragments or cells) into the subcutis of severe combined immunodeficient mice. The different tumor fragments and liposarcoma cells gave rise to fast-growing, slowgrowing, or small dormant tumors. The growth rate of the tumors correlated directly with microvessel density and correlated inversely with tumor cell apoptosis. The authors concluded that human liposarcomas are heterogeneous for induction of angiogenesis and suggest that the failure to induce angiogenesis can be responsible for the failure to xenotransplant human neoplasms into immunodeficient mice (1). Achilles et al.(4) have provided one more illustration of the “seed and soil” hypothesis. In 1889, Paget (5) proposed that the growth and spread of cancers occurred when certain favored tumor cells (seed) had a special affinity for the growth milieu provided by specific tissues or organs (soil). A current definition of the seed and soil hypothesis consists of two principles. First, neoplasms are heterogeneous and consist of cells with different biologic properties; second, the outcome of cancer growth and spread depends on multiple interactions of tumor cells with host homeostatic factors (6).

By the time of diagnosis, malignant neoplasms are biologically heterogeneous and contain multiple subpopulations of cells with different properties, including differences in morphology, growth rates, karyotypes, metabolic characteristics, antigenic or immunogenic potential, production of extracellular matrix proteins, cell surface receptors, adhesion molecules, hormone receptors, drug and radiation sensitivities, angiogenic potential, invasiveness, and the ability to metastasize (6). Angiogenic heterogeneity within a single tumor (zonal or intralesional) between different metastases even in a single organ (interlesional) and different neoplasms of the same histologic type is also documented (7, 8). For example, the implantation of murine or human cancer cells into orthotopic sites of nude mice produces progressively growing local tumors. The expression of proangiogenic molecules (and, therefore, vessel density) in the lesions is zonal, ie, intralesional heterogeneity. Small tumors (3–4 mm in diameter) express more basic fibroblast growth factor (bFGF) and interleukin 8 (IL-8) than large tumors (> 10 mm in diameter), whereas more vascular endothelial growth factor (VEGF) is expressed in large tumors. Immunostaining showed a heterogeneous distribution of angiogenic factors within the tumor; expression of bFGF and IL-8 was highest on the periphery of a large tumor, where cell division is