Chemokines and Matrix Metalloproteinases in Colorectal Cancer

Scientific exploration of cancer in the past century has primarily focused on the concept of uncontrolled growth of cancer cells with little attention to the non-neoplastic component of tumors. More recent studies brought to light the important positive and negative effects of the local host response to cancer. The tumor microenvironment is a specialized niche that provides the survival signals necessary for cancer cells to undergo proliferation, neovascularization, invasion, and metastasis. The tumor microenvironment thus provides the fertile soil for tumor growth and the selective survival advantages necessary for dissemination to other organs (Seed and Soil Hypothesis) (Fidler 2002; Paget 1889). Beginning in the early stages and continuing throughout tumor development, cancer cells secrete multiple cytokines, growth factors, and proteases to re-shape their surrounding connective tissue. This leads to the formation of a ‘reactive’ stroma that supports tumor progression by inducing reactions such as angiogenesis and inflammation. Stromal cells, such as fibroblasts, leukocytes, and endothelial cells, become activated and release additional growth factors and proteases to foster tumor growth. The extracellular matrix (ECM), another component of tumor stroma, acts as a scaffold for structural support, as well as a specialized reservoir of macromolecules, proteases and their inhibitors, growth factors, and cytokines. By inducing compositional changes in the ECM, cancer cells regulate and modify the contextual information needed for cell proliferation, migration, and invasion, thereby controlling their own fate. The reciprocal (paracrine)