Abstract A34: Role of neural mediators in the regulation of tumor dormancy and disseminated tumor cells biology
Authors: Mario Mancino, Raul Alonso, Patricia Fernandez-Nogueira, Gemma Fuster, Julio Aguirre-Ghiso, Pere Gascon, Paloma Bragado
Journal: Cancer Research (2016)

Abstract Despite considerable advances in the treatment of cancer, about 50% of patients will still eventually develop metastatic disease which remains the main cause of cancer-related death. Disseminated tumor cells (DTCs) are the precursors of metastasis and understanding their biology is one of the most important challenges for the future of cancer research. Our previous studies have shown that in the bone marrow, TGFβ2 through binding to TGFβR3 regulates DTCs quiescence through the induction of p38α MAPK. However, these DTCs dormancy may be reversed when micro-environmental conditions shift to support DTCs expansion. Nerve fibers and neural mediators are present in organs that serve as key targets for breast and head and neck cancer metastasis, including lungs and bone. In addition, neuropeptides and neurotransmitters receptors are expressed by both, nerve and cancer cells, which suggests that neurotrophic factors can act as messengers between the nervous system and DTCs and influence metastasis progression. Therefore, we hypothesized that in situations of chronic stress or inflammation, neural mediators might influence DTCs fate at secondary organs. Using head and neck (HEp3) and breast cancer (BC) models we have found that treatment with the inflammatory neuropeptide SP inhibits the expression of dormancy markers such as P-p38, DEC2 or p27 and activates ERK1/2 favoring proliferation. Moreover, dormant HEp3 cells express lower levels of the SP receptor NK1. We have previously described that the BM microenvironment induces a stable dormant phenotype in DTCs. Our studies showed that chronic exposure to SP can reverse the induction of dormancy by bone marrow mesenchymal stem cells (BMMSC) suggesting that SP production in the BM can favor DTCs escape from dormancy. Besides, using bioinformatics tools we have found that the semaphorins receptor Neuropilin 2 (NRP2), a co-receptor for TGFβ ligands, is overexpressed in basal and HER2+ breast cancer patient samples and its expression in primary tumors correlate with worst prognosis. Furthermore, we have found that NRP2 is downregulated in dormant cells and overexpressed in proliferative lung DTCs derived cell lines. In addition, breast cancer lung metastasis express higher levels of NRP2 than quiescence lung DTCs in vivo, suggesting that NRP2 might play a role in lung DTCs proliferation. Therefore, we conclude that neural mediators, such as SP and NRP2 can regulate DTCs progression from a dormant state to a proliferative state and promote metastasis formation. Citation Format: Mario Mancino, Raul Alonso, Patricia Fernandez-Nogueira, Gemma Fuster, Julio Aguirre-Ghiso, Pere Gascon, Paloma Bragado. Role of neural mediators in the regulation of tumor dormancy and disseminated tumor cells biology. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A34.