Molecular insights into cancer invasion: strategies for prevention and intervention

The diagnosis and treatment of solid tumors usually begins at a late stage when most patients already have occult or overt metastasis. Many years of cancer progression precede diagnosis of most solid tumors. Novel noncytotoxic therapeutics may be specially suited for administration during this interval. An important window of intervention can be defined as the period during which transition from a hyperproliferative state to acquisition of the capacity for invasion and metastasis occurs. Investigation of the molecular basis of invasion is uncovering strategies for delaying progression of preinvasive carcinoma and treatment of primary tumors and established metastasis. Although tumor cell invasion might not be rate limiting for the growth of metastasis, anti-invasive agents can block tumor angiogenesis and thereby indirectly block metastasis growth. Two classes of molecular anti-invasion targets exist: (a) cell surface and extracellular proteins, which mediate sensing, adhesion, and proteolysis; and (b) signal transduction pathways, which regulate invasion, angiogenesis, and proliferation. Both categories of targets yield treatment approaches that are now being tested in the clinic. Metalloproteinase inhibitors, such as BB94, are based on the recognition that metalloproteinases play a necessary role in invasion and angiogenesis. The orally active signal transduction inhibitor carboxyamidotriazole modulates non-voltage-gated calcium influx-regulated signal pathways and reversibly inhibits tumor invasion, growth, and angiogenesis. Blockade of invasion, angiogenesis, or cellular signal pathways is likely to generate a cytostatic, rather than a cytotoxic effect. Cytostatic therapy constitutes an alternative paradigm for clinical translation that may complement conventional cytotoxic therapy. For patients with newly diagnosed solid tumors, long-term cytostatic therapy could potentially create a state of metastasis dormancy or delay the time to overt relapse following cytotoxic agent-induced remission. Clinical toxicity and pharmacology using oral cytostatic agents in phase I trials and in adjuvant settings will provide an important foundation for the translation of this approach to the preinvasive carcinoma period.