Current understanding of biochemistry and molecular biology of autocrine regulation of tumor growth makes possible studies of the biological role of this mode of growth control. We propose quantitative studies of the role of autocrine regulation in models of human breast cancer micrometastases. (We define a micrometastasis as a minimally heterogeneous isolated cell population sufficiently small that the probability of phenotypic changes is negligible during experiments.) We will test the following hypotheses: 1. Autocrine mechanisms can be studied quantitatively both in vitro and in vivo. We can interpret them by use of concise mathematical models; 2. Autocrine stimulation plays a role in establishment, maintenance, and expansion of metastatic foci; 3. The degree of dependence of neoplastic growth on endocrine regulation is inversely porportional to constitutive expression of autocrine mediators; 4. Interdependence of the microscopically homogeneous regions of macroscopically heterogeneous primary tumors and metastatic foci is established and maintained by autocrine mechanisms; 5. Metastatic foci can establish different levels of regulatory independence by constitutive overproduction of autocrine mediators. In disseminated metastatic disease, a single or few overproducing foci can establish autocrine independence of the panmetastatic system; 6. Growth of metastatic systems can be controlled by therapeutic manipulations of the autocrine regulatory mechanisms. We propose that the mass of autocrinely controlled tumor is a function not only of time, but also of its own mass; this establishes positive feedback regulation of growth. We formulate this concept in a simple phenomenological mathematical model and propose experiments to test the model and the proposed hypotheses. These studies will establish a framework for quantitative comparisons of tumors on the basis of dependence of their proliferation on autocrine functions and demonstrate to what extent growth in models of human breast cancer can be manipulated by controlling autocrine functions.
