Regulation of tumor recurrence by stress activated neutrophils

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Abstract Complete removal of tumor lesions with surgical resection is the treatment of choice for patients with early stages of non-small cell lung cancer (NSCLC), as well as with many other types of cancer. It often results in cancer cure. However, substantial proportion of patients develops local or distant recurrences within several years. It is widely accepted that small numbers of tumor cells disseminate from primary tumor site early on during tumor development and persist in dormant state until cells re-enter the cell cycle. Cancer cell dormancy can also be the response to radiation and chemotherapy associated with DNA damage, which explains recurrence even after a complete response to therapies. Those dormant cells usually have characteristics of senescent cells, thus this phenomenon is often referred as “therapy-induced senescence” (TIS). Although signaling in dormant and senescent tumor cells is relatively well understood, much less is known about the mechanisms that evade dormancy to form local recurrence or distant metastases years after complete elimination of primary tumor. In this application, we model tumor cell dormancy by using two experimental systems. The first is the induction of dormancy by regulation of the expression of tumor suppressor gene p53 in lung cancer cells. This model allows for the study of tumor dormancy, which is not induced by treatment with chemo- or radiation therapy and may reflect changes in tumor cells after dissemination to tissues. The second is the model of TIS in mouse lung and human ovarian cancer treated with chemotherapy. Our preliminary studies demonstrated that neutrophils were able to induce proliferation of dormant tumor cells. We found that this effect could be caused by neuroendocrine adrenergic hormones as the result of prolonged stress. We suggest a novel concept of regulation of tumor recurrence. We propose that adrenergic hormones cause a rapid release and autocrine/paracrine signaling by S100A8/A9 proteins heterodimer leading to up-regulation of myeloperoxidase (MPO) in neutrophils. MPO and ROS contributed to formation of oxidized lipids by neutrophils, which directly activated dormant tumor cells. The main goal of this study is to identify the mechanism of recurrence in cancer and to determine therapeutic targeting strategy to control this process and ultimately eliminate dormant tumor cells to prevent recurrence. To achieve this goal, we propose the following specific aims. Specific Aim 1. To identify specific mechanisms of neutrophil-mediated reactivation of dormant tumor cells. Specific Aim 2. To determine signaling in dormant tumor cells responsible for their reactivation, to identify clinical significance and therapeutic targeting of reactivation of dormant tumor cells.