Tumor Cells And Stromal Interactions

Angiogenesis

Angiogenesis, the growth of new capillary blood vessels, is a prerequisite for cellular growth beyond the size restriction dictated by oxygen and nutrient diffusion. Angiogenesis is regulated by growth factors and properties of the extracellular matrix.9,10 Promoters of angiogenesis include basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial growth factor (VEGF), and angiopoietin 1. In contrast, endogenous proteins such as angio-statin, endostatin, pigment epithelium derived factor (PEDF), and angiopoietin 2, prevent vascular cells from responding to a wide spectrum of angiogenic factors. The structure of newly formed blood vessels differs from that of normal vessels. The main differences include the cellular components, the properties and integrity of the basement membrane, and permeability. These elements facilitate the leakage and passage of cancer cells into the circulation. Microvessel density and histological arrangement of blood vessels in the tissue are an independent prognostic indicator of the risk for future development of metastasis. Additionally, angiogenesis is necessary for the growth of cells in the new metastatic foci. To survive, tumor cells must gain access to the vasculature within the pri mary tumor, survive transit, dwell for a time in the microvasculature of the target organ, exit from this vasculature, grow in the target organ, and induce an-giogenesis (Figures 4.2 and 4.3).

Cellular Factors

Cell-to-cell interactions and cell-to-stroma interactions are very important during the invasive stages. The homeostasis of surface receptors and the adhesion molecules, integrins and cadherins, favors tissue stability and integrity, whereas the loss or alteration of these cell surface proteins has been associated with increased metastatic potential.11 Downregulation of gene expression of E-cadherin has been correlated with increased invasiveness and metastatic potential. Another mechanism that facilitates invasion is degradation of surface protein complexes by mutated gene products.

Tumor cell migration is necessary for the initiation of the metastatic cascade. The interaction of surface receptor proteins and components of the extracellular matrix such as laminin, collagens, fibronectin, and vitronectin regulates the shape, polarity, and migration of cells.12 Some members of the integrin family of adhesion molecules play a fundamental role in the angiogenesis and invasion.13 Overexpression of integrin avp3 mediates cellular adhesion with the ex

Regression and arrested growth Dissemination Metastasis

Initiation

Regression and arrested growth Dissemination Metastasis

Initiation

Acquired transformed phenotypes

Clinical detection

Acquired transformed phenotypes

Clinical detection

FIGURE 4.1. Tumor progression. The diagram shows that the events of progression, invasion, dissemination, and metastasis are associated with acquired transformed phenotypes.

Tumor growth

Tumor cells and extracellular matrix

Angiogenesis

Tumor growth

Tumor cells and extracellular matrix

FIGURE 4.2. Angiogenesis is a required step for survival of the tumor, invasion, and dissemination.

Angiogenesis

Homing factors ff-ยป

Host response

Metastasis

FIGURE 4.2. Angiogenesis is a required step for survival of the tumor, invasion, and dissemination.

tracellular matrix proteins leading to changes in cell shape and increased cell motility. Growth factors that stimulate tumor cell motility include insulin growth factor (IGF), hepatic growth factor (HGF), fibroblast growth factor (FGF), and transforming growth factor p (TGF-p). These factors may play a role in the "homing" of the tumor cell to secondary sites. Cell-matrix interaction also leads to transcription and expression of genes with increased amounts of proteases and disruption of the balance between activated matrix met-alloproteinases (MMPs) and free endogenous tissue inhibitors of metalloproteinases (TIMPs) that facilitate invasion and metastasis.14-16

RB and p16, are altered in diverse tumor types, and others are selectively modified in particular tumors such as those of the von Hippel-Lindau (VHL gene) syndrome.19 Because of heterogeneity of gene silencing and expression, most primary tumors contain subpopulations of metastastic and nonmetastatic cells. Genes differently expressed in cancer cells that reach the bloodstream have the effect of inducing or suppressing metastasis.

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