The immune system has a regulatory role in cancer biology. that role is usually thought to be elimination of tumor cells. However, we previously showed that the number of circulating polymorphonuclear cells (PMNs) increases, by up to 50-fold, in 13762NF mammary adenocarcinoma tumor- bearing rats. Neutrophilia was proportional to metastatic potential, but PMNs did not kill nor inhibit tumor cell growth. Rather, tumor-elicited PMNs secreted high levels of basement membrane-degrading proteases which increase tumor cell invasion in an in vitro invasion assay. When tumor- elicited PMNs, but not normal PMNs, were co-injected into syngeneic rats with 13762NF cell clones, the number of metastases rose 2- to 25-fold. Our hypothesis is that polymorphonuclear neutrophils can degrade basement membranes for tumor cells, increasing metastasis by breast cancer cells. The overall goals of this project are to: 1) understand the mechanisms involved in eliciting neurophilia; and 2) test the hypothesis that neutrophils enhance metastatic ability of breast cancer. Using the 13762NF rat mammary adenocarcinoma, we will determine the mechanisms involved in eliciting neutrophilia; what markers distinguish tumor elicited PMNs from normal (circulating or artificially activated) PMNs; and determine whether tumor-elicited neutrophils from all tumors are capable of enhancing cancer invasion and metastasis. To answer these questions, we will accomplish three Specific Aims: 1) to identify specific markers which distinguish tumor-elicited from circulating or activated neutrophils; 2) to determine what factors are produced by tumor cells which recruit neutrophils (cause neutrophilia) and/or activate tumor elicited neutrophils; and 3) to determine whether all tumor- elicited PMNs are capable of increasing invasiveness and metastasis of 13762NF rat mammary adenocarcinoma cell clones.
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