Invasion and Metastasis Invasive Growth and the Tumor Microenvironment

The spread of primary tumors to other sites in the body to form metastasis is responsible for the majority of cancer-related deaths. Growth of occult metastasis is dependent on cancer cells invading the basement membrane surrounding the primary tumor and entering the lymphatic or blood system. Within the circulation, cells must be able to resist anoikis (programed cell death due to loss of anchorage), evade the immune response, and overcome shear stress before arresting within the capillary bed of the distant site. At this site, the cell must either proliferate within the vasculature or extravasate into the surrounding tissue, survive, divide, and coopt the extant vascular system. These multiple, essential, and interrelated steps explain why very few clinically relevant metastasis occur despite the fact that tumors can shed millions of cancer cells daily into the vasculature.

Although much remains unclear, it is apparent that during invasion and metastasis fundamental changes occur in the manner in which cells respond to and modify their local environment. Invasive growth is characterized by unregulated tissue remodeling in which normal tissue is replaced by tumor tissue. The actions of malignant and neighboring cells, responding to soluble factors released by the tumor, result in characteristic changes in the surrounding stroma. The tumor stroma microenvironment is rich in endothelial cells, smooth muscle cells, and myelofibroblasts.149 Under the influence of the tumor, these cells proliferate, migrate, and differentiate, releasing enzymes that degrade the surrounding extracellular matrix as well as growth factors and cytokines that can act in a paracrine fashion, promoting tumor growth and invasion. In addition, the release of chemotactic factors leads to the accumulation and activation of dendritic and inflammatory cells, thereby increasing levels of local cytokines. Defining the changes in the manner with which tumors interact with their microenvironment is therefore key to understanding the mechanisms underlying invasive growth. Adhesion Molecules

Adhesion molecules play a major role in the interchange of signals between the cell and its environment. Differential regulation of several classes of adhesion molecules has been implicated in invasion and metastasis of which perhaps the best characterized are cadherins and integrins.

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