neuropeptide-y and Ovarian-Neoplasms

Cisplatin is the most effective and widely used chemotherapeutic agent for many types of cancer. Unfortunately, its clinical use is limited by its adverse effects, notably bone marrow suppression leading to abnormal hematopoiesis. We previously revealed that neuropeptide Y (NPY) is responsible for the maintenance of hematopoietic stem cell (HSC) function by protecting the sympathetic nervous system (SNS) fibers survival from chemotherapy-induced bone marrow impairment. Here, we show the NPY-mediated protective effect against bone marrow dysfunction due to cisplatin in an ovarian cancer mouse model. During chemotherapy, NPY mitigates reduction in HSC abundance and destruction of SNS fibers in the bone marrow without blocking the anticancer efficacy of cisplatin, and it results in the restoration of blood cells and amelioration of sensory neuropathy. Therefore, these results suggest that NPY can be used as a potentially effective agent to improve bone marrow dysfunction during cisplatinbased cancer therapy. [BMB Reports 2017; 50(8): 417-422].

Topics: Animals; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cisplatin; Female; Hematopoietic Stem Cells; Heterografts; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neuropeptide Y; Ovarian Neoplasms; Random Allocation; Receptors, Neuropeptide Y

At 2 years of age, 100% (23/23) of ERbeta(-/-) female mice have developed large pituitary and ovarian tumors. The pituitary tumors are gonadotropin-positive and the ovarian tumors are sex cord (less differentiated) and granulosa cell tumors (differentiated and estrogen secreting). No male mice had pituitary tumors and no pituitary or ovarian tumors developed in ERalpha(-/-) mice or in ERalphabeta(-/-) double knockout mice. The tumors have high proliferation indices, are ERalpha-positive, ERbeta-negative, and express high levels of nuclear phospho-SMAD3. Mice with granulosa cell tumors also had hyperproliferative endometria. The cause of the pituitary tumors appeared to be excessive secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus resulting from high expression of NPY. The ovarian phenotype is similar to that seen in mice where inhibin is ablated. The data indicate that ERbeta plays an important role in regulating GnRH secretion. We suggest that in the absence of ERbeta, the proliferative action of FSH/SMAD3 is unopposed and the high proliferation leads to the development of ovarian tumors. The absence of tumors in the ERalphabeta(-/-) mice suggests that tumor development requires the presence of ERalpha.

Topics: Aging; Animals; Cell Proliferation; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Ki-67 Antigen; Male; Mice; Mice, Knockout; Neoplasms, Second Primary; Neuropeptide Y; Ovarian Neoplasms; Pituitary Neoplasms; Sex Characteristics