Interactions between the extracellular matrix (ECM) and the neoplastic cells they envelop are thought to play a fundamental role in those cells' ability to invade, one of the key events in the metastatic cascade. Cellular transport of amino acids, in turn, is known to be mediated by functionally distinct membrane transport systems and is modulated by substrate bioavailability in the microenvironment. We postulate that certain advantages enjoyed by a neoplastic cell population over their normal counterparts (for example, increased proliferating capability and invasiveness across ECM barriers) are linked to changes in the cells' differential control of amino acid transport (aaT) via host ECM-tumor cell generated signals. Our studies suggest that active transport of neutral amino acids modulates a cells' functional behavior among phenotypically distinct human transformed cell types, irrespective of whether they are categorized as a sarcoma, melanoma, or carcinoma. We present preliminary laboratory evidence which has lead us to formulate a series of working hypotheses as follows: 1. aaT systems operating in both non-transformed and transformed human cells exhibit differential transport kinetics; 2. adaptive regulation of certain amino acids via cell-specific aaT systems alters a cell's ability to invade human ECM; and 3. aaT induction involves changes both at the cellular and molecular levels. This report, therefore, provides experimental support, and suggests a possible mechanism, to explain how neutral amino acids, acting as nutrient signalling factors (along with other biologic elements) within the cell milieu, have the capability of regulating the phenotypic nature of human neoplastic cells. © 1995.