Cancer Metastasis and Angiogenesis: an Imbalance of Positive and Negative Regulation

Lance A. Liotta, Patricia S. Steeg, and William G. Stetler-Stevenson Laboratory of Pathology National Cancer Institute National Institutes of Health Bethesda, Maryland 20892 The most life-threatening aspects of the oncogenic pro- cess are invasion and metastasis. Even though the clinical significance of such expression of the malignant pheno- type has been well appreciated, advances in understand- ing the molecular mechanisms involved in metastasis have lagged behind other developments in the cancer field. Progress has been hindered by the sheer complexity of this multistep, tumor-host interaction that also encom- passes angiogenic and immunologic mechanisms. To tackle the problem, investigators have separated invasion and metastasis into a series of defined, sequential steps, and focused on one step at a time. For each step, new ex- perimental models had to be developed, and a combined effort using the disciplines of cell biology, protein bio- chemistry, and molecular genetics has now resulted in a surge of new information. General themes are emerging that yield new strategies for prognosis and therapy of hu- man metastatic cancer. A group of coordinated cellular processes is responsi- ble for metastasis. Furthermore, it is now clear that nega- tive regulatory processes may be just as important as positive ones. Some genetic changes result in an im- balance of growth regulation, leading to uncontrolled proliferation. However, unrestrained growth does not, by itself, result in invasion and metastasis. The latter pheno- type may therefore require additional genetic changes. Thus, tumorigenicity and metastatic potential have both overlapping and separate features. Invasion and metasta- sis can be facilitated by proteins that stimulate tumor cell attachment to host cellular or extracellular matrix deter- minants, tumor cell proteolysis of host barriers such as the basement membrane, tumor cell locomotion, and tumor cell colony formation in the target organ for metastasis. Facilitory proteins may act at many levels intracellularly or extracellularly, but are counterbalanced by factors that can block their production, regulation, or action. A com- mon theme has emerged: in addition to loss of growth control, an imbalanced regulation of motility and proteoly- sis appears to be required for invasion and metastasis. Moreover, these same functions are also necessary for angiogenesis. Angiogenesis by normal endothelial cells and metastasis by tumor cells are functionally similar but differ in their regulation. Metastatic Cells Do Not Constitute a Minor Subpopulation The process of metastasis involves a cascade of linked, sequential steps involving multiple host-tumor interac- tions (Fidler and Hart, 1982; Schirrmacher, 1985; Liotta et