In reference to NOT-OD-09-058 (Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications), we submit this Competitive Revision to the parent grant entitled """"""""Tumor metastasis: Biobehavioral mechanisms (R01CA110793)."""""""" Psychosocial stress can elicit alterations of immunological, neurochemical, and endocrinological functions. To date, most of the research dealing with stress and tumor growth has focused on suppressed immunity;however, progressive growth of cancer is influenced by many other factors including tumor cell migration and invasion. There has been little investigation of the effect of stress hormones such as norepinephrine and epinephrine on these key processes that are required for metastasis. Focal adhesion kinase (FAK) is one of the key factors involved in tumor cell migration and invasion. We have compelling preliminary data that one of the stress hormones, norepinephrine, can directly activate FAK and promote tumor growth and these effects can be blocked by using inhibitors of beta-adrenergic receptors. Furthermore, our preliminary data suggest that FAK plays a key role in ovarian cancer migration and invasion. The parent grant has determined the underlying mechanisms and pathways by which stress hormones can affect ovarian cancer migration and invasion using in vitro assays and we have experimentally identified the in vivo effects of chronic stress on ovarian cancer progression using a well-characterized mouse model of ovarian carcinoma and are examining the associations between psychosocial factors and FAK in human ovarian cancers. During this work, we have made novel observations that chronic stress and associated increases in catecholamines protect tumor cells from undergoing anoikis, but the exact mechanisms are not well known. In the present supplement, we seek to determine whether chronic stress and associated neuroendocrine dynamics could protect ovarian cancer cells from anoikis, and to identify the underlying signaling pathways. The proposed supplement will advance the goals and objectives of the parent grant by allowing us to examine in vitro mechanisms of norepinephrine mediated protective effects against anoikis and determine in vivo effects of stress on protection of tumor cells in ascites against apoptosis (in vivo reflection of anoikis avoidance by tumor cells). Findings of this study could lead to identification of a completely new mechanism by which chronic stress affects tumor cell survival and growth, and therefore may lead to new behavioral and pharmacological therapeutic approaches.
Project narrative FAK is known to promote tumor cell survival and may play a significant role in avoidance of anoikis. We have previously demonstrated that catecholamines promote ovarian carcinoma growth via stimulation of angiogenic pathways. However, the mechanism by which invading tumor cells survive anoikis remains largely unknown. The proposed work here will advance the goals and objectives of the parent grant by allowing us to examine in vitro mechanisms of norepinephrine mediated protective effects against anoikis and determine in vivo effects of stress on FAK and Src and protection of cells in ascites against apoptosis (in vivo reflection of anoikis avoidance by tumor cells).
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|Stone, Rebecca L; Baggerly, Keith A; Armaiz-Pena, Guillermo N et al. (2014) Focal adhesion kinase: an alternative focus for anti-angiogenesis therapy in ovarian cancer. Cancer Biol Ther 15:919-29|
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|Cohen, Lorenzo; Cole, Steven W; Sood, Anil K et al. (2012) Depressive symptoms and cortisol rhythmicity predict survival in patients with renal cell carcinoma: role of inflammatory signaling. PLoS One 7:e42324|
|Bottsford-Miller, Justin N; Coleman, Robert L; Sood, Anil K (2012) Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol 30:4026-34|
|Nick, Alpa M; Stone, Rebecca L; Armaiz-Pena, Guillermo et al. (2011) Silencing of p130cas in ovarian carcinoma: a novel mechanism for tumor cell death. J Natl Cancer Inst 103:1596-612|
|Han, Hee Dong; Mora, Edna M; Roh, Ju Won et al. (2011) Chitosan hydrogel for localized gene silencing. Cancer Biol Ther 11:839-45|
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