Physical Activity and Natural Anti-VIP Antibodies: Potential Role in Breast and Prostate Cancer Therapy Milena Veljkovic 1 , Violeta Dopsaj 2 , Milivoj Dopsaj 3 , Donald R. Branch 4 , Nevena Veljkovic 5 , Maria M. Sakarellos-Daitsiotis 6 , Veljko Veljkovic 5 *, Sanja Glisic 5 , Alfonso Colombatti 7 1 Sveti Sava Hospital, Belgrade, Serbia, 2 Institute of Medical Biochemistry, Clinical Centre of Serbia, Belgrade, Serbia, 3 Faculty of Sport and Physical Education, University of Belgrade, Belgrade, Serbia, 4 Canadian Blood Services, Toronto, Ontario, Canada, 5 Center for Multidisciplinary Research, Institute of Nuclear Sciences VINCA, Belgrade, Serbia, 6 Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, Ioannina, Greece, 7 Divisione di Oncologia Sperimentale, Centro di Riferimento Oncologico CRO-IRCCS, Aviano, Italy Abstract Background: There is convincing evidence from numerous clinical and epidemiological studies that physical activity can reduce the risk for breast and prostate cancer. The biological mechanisms underlying this phenomenon remain elusive. Herein we suggest a role for naturally produced antibodies reactive with the vasoactive intestinal peptide (VIP) in the suppression of breast and prostate cancer, which we believe could offer a possible molecular mechanism underlying control of these cancers by physical exercise. Methodology and Results: We found that sera from individuals having breast and prostate cancers have decreased titers of VIP natural antibodies as demonstrated by a lower reactivity against peptide NTM1, having similar informational and structural properties as VIP. In contrast, sera collected from elite athletes, exhibited titers of natural NTM1-reactive antibodies that are significantly increased, suggesting that physical activity boosts production of these antibodies. Significance: Presented results suggest that physical exercise stimulates production of natural anti-VIP antibodies and likely results in suppression of VIP. This, in turn, may play a protective role against breast and prostate cancers. Physical exercise should be further investigated as a potential tool in the treatment of these diseases. Citation: Veljkovic M, Dopsaj V, Dopsaj M, Branch DR, Veljkovic N, et al. (2011) Physical Activity and Natural Anti-VIP Antibodies: Potential Role in Breast and Prostate Cancer Therapy. PLoS ONE 6(11): e28304. doi:10.1371/journal.pone.0028304 Editor: Jean-Marc A. Lobaccaro, Clermont Universite ´, France Received June 9, 2011; Accepted November 5, 2011; Published November 30, 2011 Copyright: ß 2011 Veljkovic et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Ministry of Science and Technological Development of the Republic of Serbia (Grant no. 173001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: vv@vinca.rs Introduction The vasoactive intestinal peptide (VIP) is a pleiotropic peptide important in many physiologic functions, including glucose homeostasis, neuroprotection, memory, gut function, modulation of the immune system and circadian function. In addition, there are numerous evidences that (VIP) and its receptors, which are highly expressed in breast tumor cells [1],[2],[3],[4],[5],[6],[7],[8], play an important role in the pathogenesis of breast cancer. VIP functions as an autocrine growth factor [8],[9] and regulates proliferation, survival, and differentiation in human breast cancer cells [10]; it has proangiogenic functions [11] in breast cancer. VIP also induces transactivation of epidermal growth factor receptor (EGFR) and human epidermal growth factor-2 receptor (HER2) and increases expression of c-fos, c-jun and c-myc oncogenes [2],[12],[13]. There also is mounting evidence that VIP is involved in the pathogenesis of prostate cancer. VIP increases the expression of the major angiogenic factor VEGF [14] and acts as a proangiogenic factor [15],[16],[17]. VIP increases neuroendocrine differentiation [18] and stimulates interleukin-6 production [19] and prostate-specific antigen (PSA) secretion in prostate cancer [20]. In addition, VIP stimulates HER2 transphosphorylation in androgen-independent prostate cancer cells [17], stimulates their invasive capacity [21] and contributes to prostate cancer pathogenesis by induction of malignant transformation [22]. VIP antagonists suppress the release of prostate-specific antigen (PSA) [23] and inhibit growth of breast and prostate cancer cells [24],[25],[26],[27],[28],[29]. Taken together, these observations strongly support the notion that VIP plays an important role in breast and prostate cancer pathogenesis and suggests that elevated concentrations of VIP in the circulation may represent a risk factor for these cancer types. VIP is elevated in plasma after aerobic exercise [30],31[31], [32],[33],[34],[35],[36] suggesting that physical activity represents a potential stimulus for VIP autoantibody formation [37],[38]. Because of the immunomodulatory and neuromodulatory activ- ities of VIP, circulating levels of this peptide are under tight control and natural anti VIP autoantibodies are potent modifiers of its biological actions and important regulators of its circulating level [39],[40],[41],[42],[43]. However, the antigenic stimulus leading to the formation of these autoantibodies has not been identified yet. It was previously shown that structural and informational similarity, represented by the informational spectrum frequencies, is essential for the immunological cross-reactivity between VIP and HIV-1 gp120 [44],[45],[46],[47]. This analysis revealed that PLoS ONE | www.plosone.org 1 November 2011 | Volume 6 | Issue 11 | e28304