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Targeting tumor microenvironment by natural agents for the inhibition of prostate cancer progression
Emerging evidence has demonstrated that tumor microenvironment plays a critical role in the regulation of tumor development and progression.(1, 2) The stromal cells surrounding cancer cells could provide both positive and negative signals to cancer cells, and thereby regulate cancer cell proliferation, invasion, and metastasis. Therefore, targeting specific molecular processes within the tumor microenvironment could be an efficient therapeutic strategy for the treatment of cancers. In prostate cancer (PCa), the bone is the first and predominant site where PCa metastasis is often found. The PCa cells after homing to the bone utilize the local cytokine machinery to stimulate bone remodeling which facilitates both the homing and the subsequent tumor growth within the bone. During bone remodeling, osteoclasts and osteoblasts are main bone cells which are critically involved in bone resorption and new bone formation. In the processes of bone metastasis, PCa cells initiate a crosstalk with pre-osteoclasts and pre-osteoblasts within the tumor microenvironment, resulting in the differentiation of osteoclasts and osteoblasts through the up-regulation of RANKL, RUNX2 and osteopontin signaling (see Figure 1). Through this initial crosstalk, metastatic PCa cells promote bone remodeling during the formation of metastatic tumors in the bone. Therefore, molecular targeting of osteoclasts and osteoblasts within the tumor microenvironment could be a novel therapeutic strategy for the inhibition of PCa bone metastasis through the suppression of bone remodeling.
In order to understand the complexities of the regulatory processes of the differentiation of osteoclasts and osteoblasts, we investigated the effects of several natural agents including isoflavone - which we have previously shown to regulate RANKL signaling in osteoclasts. By cellular and molecular experimental approaches, we have discovered that two natural agents, such as formulated isoflavone from soybean and 3,3’-diindolylmethane (BR-DIM) mainly from Cruciferae such as broccoli, exerted their significant inhibitory effects on the differentiation of both osteoclast and osteoblast in bone cell culture alone or in bone cells co-cultured with PCa cells which were mediated through the regulation of osteoclast and osteoblast signaling.(3) Isoflavone and BR-DIM also inhibited PCa cell proliferation by targeting multiple signaling pathways including AR/PSA, Akt/cyclin/p27, RANKL/MITF, and also microRNA (miRNA) mediated regulation of Epithelial-to-Mesenchymal Transition (EMT) signaling (see Figure 2). Therefore, isoflavone and BR-DIM with their multi-targeted effects could be useful for the prevention and inhibition of bone remodeling, and thus the inhibition of PCa bone metastasis.
It is obvious that treatment with natural agents alone may not be optimal enough to eliminate PCa cells both in the primary and in the metastatic sites. However, our present discovery together with our previous reports and several findings by other investigators suggests that natural agents could be useful in combination with conventional agents to optimize the efficacy of conventional therapeutics.(4-6) Because of the non-toxic and anti-cancer features of natural agents, better treatment outcome and lower systemic toxicity could be achievable through the combination treatment.
In conclusion, we believe that isoflavone and BR-DIM with their abilities in “conditioning the tumor microenvironment” could be a novel strategy for designing combination treatment with conventional cancer therapeutics both for the prevention and inhibition of PCa progression by attenuating bone metastatic mechanism(s), which opens a newer avenue toward alternative cancer therapy.
Figure 1. Prostate cancer stimulated bone remodeling. (click thumbnail to enlarge)
Figure 2. The effects of isoflavone and BR-DIM on bone remodeling and prostate cancer bone metastasis. (click thumbnail to enlarge)
References:
- Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer 2011;11:411-25.
- Karlou M, Tzelepi V, Efstathiou E. Therapeutic targeting of the prostate cancer microenvironment. Nat Rev Urol 2010;7:494-509.
- Li Y, Kong D, Ahmad A, Bao B, Sarkar FH. Targeting bone remodeling by isoflavone and 3,3'-diindolylmethane in the context of prostate cancer bone metastasis. PLoS One 2012;7:e33011.
- Li Y, Kucuk O, Hussain M, Abrams J, Cher ML, Sarkar FH. Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer. Cancer Res 2006;66:4816-25.
- Sarkar FH, Li Y. Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res 2006;66:3347-50.
- Stearns ME, Amatangelo MD, Varma D, Sell C, Goodyear SM. Combination therapy with epigallocatechin-3-gallate and doxorubicin in human prostate tumor modeling studies: inhibition of metastatic tumor growth in severe combined immunodeficiency mice. Am J Pathol 2010;177:3169-79.
Written by:
Yiwei Li,1 Dejuan Kong,1 Aamir Ahmad,1 Bin Bao,1 and Fazlul H. Sarkar1,2 as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Departments of 1Pathology and 2Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
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