Molecular targets of pomegranate (Punica granatum) in preventing cancer metastasis

Document Type: Review Article

Author

Cancer Prevention Research Center, Shahroud University of Medical Sciences, Shahroud, Iran

Abstract

Metastasis is the primary cause of mortality and morbidity among cancer patients and accounts for about 90% of cancer deaths. The most common types of treatment for cancer metastasis are chemotherapy and radiotherapy. However, such therapy has many serious side effects that could diminish the quality of life in patients. There is increased appreciation by the scientific community that natural compounds can be potential weapons in fighting against cancer. Interestingly, much evidence shows that pomegranate (Punica granatum) has great potential to inhibit tumor growth and metastasis. In this review, we discussed the molecular targets of pomegranate, specifically, those that are prerequisite for cancer metastasis. The search was performed in Google Scholar, Medline, Scopus, and PubMed using keywords such as metastasis, pomegranate, and signaling pathways. Some of the most important papers from the search results were included. Based on recent studies, some molecules, including those involved in cell-cell and cell-extracellular matrix adhesions, are affected by pomegranate. The other targets of pomegranate are modulators of cytoskeleton dynamics and regulators of cancer cell anoikis and chemotaxis. Furthermore, the antimetastatic effect of pomegranate may be attributed to molecular changes of the extracellular matrix. Pro-inflammatory and pro-angiogenic molecules are the other targets of pomegranate regarding cancer metastasis. A wide variety of molecules can be targeted by pomegranate to suppress tumor metastasis. A better understanding of the molecules regulated by pomegranate is needed to provide a rational basis for its clinical application.

Keywords

Main Subjects


1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.
2. Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncog 2013;18:43-73.
3. Naderi-Meshkin H, Ahmadiankia N. Cancer metastasis versus stem cell homing: Role of platelets. J Cell Physiol 2018;233:9167-9178.
4. Pearce A, Haas M, Viney R, Pearson SA, Haywood P, Brown C, et al. Incidence and severity of self-reported chemotherapy side effects in routine care: A prospective cohort study. PLoS One 2017;12:e0184360.
5. Kunnumakkara AB. Anticancer properties of fruits and vegetables: A scientific review: World Scientific; 2014.
6. Paller CJ, Ye X, Wozniak PJ, Gillespie BK, Sieber PR, Greengold RH, et al. A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis 2013;16:50-55.
7. Shanmugam MK, Lee JH, Chai EZ, Kanchi MM, Kar S, Arfuso F, et al. Cancer prevention and therapy through the modulation of transcription factors by bioactive natural compounds. Semin Cancer Biol 2016;40-41:35-47.
8. Nunez-Sanchez MA, Gonzalez-Sarrias A, Garcia-Villalba R, Monedero-Saiz T, Garcia-Talavera NV, Gomez-Sanchez MB, et al. Gene expression changes in colon tissues from colorectal cancer patients following the intake of an ellagitannin-containing pomegranate extract: a randomized clinical trial. J Nutr Biochem 2017;42:126-133.
9. Syed DN, Chamcheu JC, Adhami VM, Mukhtar H. Pomegranate extracts and cancer prevention: molecular and cellular activities. Anticancer Agents Med Chem 2013;13:1149-1161.
10.    Holland D, Hatib K, Bar-Ya’akov I. Pomegranate: Botany, horticulture, breeding horticultural reviews, Vol. 35, Edited by Jules Janick Copyright & John Wiley & Sons. Inc; 2009.
11.    Wang D, Ozen C, Abu-Reidah IM, Chigurupati S, Patra JK, Horbanczuk JO, et al. Vasculoprotective effects of pomegranate (Punica granatum L.). Front Pharmacol 2018;9:544-558.
12.    Wu S, Tian L. Diverse phytochemicals and bioactivities in the ancient fruit and modern functional food pomegranate (Punica granatum). Molecules 2017;22:pii: E1606.
13.    Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem 2000;48:4581-4589.
14.    González-Sarrías A, García-Villalba R, Núñez-Sánchez MÁ, Tomé-Carneiro J, Zafrilla P, Mulero J, et al. Identifying the limits for ellagic acid bioavailability: a crossover pharmacokinetic study in healthy volunteers after consumption of pomegranate extracts. J Func Foods 2015;19:225-235.
15.    Tomas-Barberan FA, Gonzalez-Sarrias A, Garcia-Villalba R, Nunez-Sanchez MA, Selma MV, Garcia-Conesa MT, et al. Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status. Mol Nutr Food Res 2017;61.
16.    Heber D. Pomegranate ellagitannins.  2011.
17.    Tomas-Barberan FA, Garcia-Villalba R, Gonzalez-Sarrias A, Selma MV, Espin JC. Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J Agric Food Chem 2014;62:6535-6538.
18.    Cerdá B, Espín JC, Parra S, Martínez P, Tomás-Barberán FA. The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy–6H–dibenzopyran–6–one derivatives by the colonic microflora of healthy humans. Eur J Nutr 2004;43:205-220.
19.    Cerdá B, Soto C, Albaladejo M, Martinez P, Sanchez-Gascon F, Tomás-Barberán F, et al. Pomegranate juice supplementation in chronic obstructive pulmonary disease: a 5-week randomized, double-blind, placebo-controlled trial. Eur J Clin Nutr 2006;60:245-253.
20.    Garcia-Villalba R, Vissenaekens H, Pitart J, Romo-Vaquero M, Espin JC, Grootaert C, et al. Gastrointestinal simulation model TWIN-SHIME shows differences between human urolithin-metabotypes in gut microbiota composition, pomegranate polyphenol metabolism, and transport along the intestinal tract. J Agric Food Chem 2017;65:5480-5493.
21.    Espin JC, Gonzalez-Barrio R, Cerda B, Lopez-Bote C, Rey AI, Tomas-Barberan FA. Iberian pig as a model to clarify obscure points in the bioavailability and metabolism of ellagitannins in humans. J Agric Food Chem 2007;55:10476-10485.
22.    Cerda B, Tomas-Barberan FA, Espin JC. Metabolism of antioxidant and chemopreventive ellagitannins from strawberries, raspberries, walnuts, and oak-aged wine in humans: identification of biomarkers and individual variability. J Agric Food Chem 2005;53:227-235.
23.    Mertens-Talcott SU, Jilma-Stohlawetz P, Rios J, Hingorani L, Derendorf H. Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum l.) polyphenols after ingestion of a standardized extract in healthy human volunteers. J Agric Food Chem 2006;54:8956-8961.
24.    Seeram NP, Henning SM, Zhang Y, Suchard M, Li Z, Heber D. Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours. J Nutr 2006;136:2481-2485.
25.    Seeram NP, Lee R, Heber D. Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clin Chim Acta 2004;348:63-68.
26.    Verotta L, Panzella L, Antenucci S, Calvenzani V, Tomay F, Petroni K, et al. Fermented pomegranate wastes as sustainable source of ellagic acid: Antioxidant properties, anti-inflammatory action, and controlled release under simulated digestion conditions. Food Chem 2018;246:129-136.
27.    Lei F, Xing DM, Xiang L, Zhao YN, Wang W, Zhang LJ, et al. Pharmacokinetic study of ellagic acid in rat after oral administration of pomegranate leaf extract. J Chromatogr B Analyt Technol Biomed Life Sci 2003;796:189-194.
28.    Pereira de Melo IL, de Oliveira ESAM, Yoshime LT, Gasparotto Sattler JA, Teixeira de Carvalho EB, Mancini-Filho J. Punicic acid was metabolised and incorporated in the form of conjugated linoleic acid in different rat tissues. Int J Food Sci Nutr 2018:1-11.
29.    Salwe KJ, Sachdev DO, Bahurupi Y, Kumarappan M. Evaluation of antidiabetic, hypolipedimic and antioxidant activity of hydroalcoholic extract of leaves and fruit peel of Punica granatum in male Wistar albino rats. J Nat Sci Biol Med 2015;6:56-62.
30.    Khajebishak Y, Payahoo L, Alivand M, Alipour B. Punicic acid: A potential compound of pomegranate seed oil in Type 2 diabetes mellitus management. J Cell Physiol 2019;234:2112-2120.
31.    Boozari M, Hosseinzadeh H. Natural medicines for acute renal failure: A review. Phytother Res 2017;31:1824-1835.
32.    Rathod NR, Biswas D, Chitme HR, Ratna S, Muchandi IS, Chandra R. Anti-urolithiatic effects of Punica granatum in male rats. J Ethnopharmacol 2012;140:234-238.
33.    Arunkumar J, Rajarajan S. Study on antiviral activities, drug-likeness and molecular docking of bioactive compounds of Punica granatum L. to Herpes simplex virus - 2 (HSV-2). Microb Pathog 2018;118:301-309.
34.    Haidari M, Ali M, Ward Casscells S, 3rd, Madjid M. Pomegranate (Punica granatum) purified polyphenol extract inhibits influenza virus and has a synergistic effect with oseltamivir. Phytomedicine 2009;16:1127-1136.
35.    Yuan T, Ma H, Liu W, Niesen DB, Shah N, Crews R, et al. Pomegranate’s Neuroprotective Effects against Alzheimer’s Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites. ACS Chem Neurosci 2016;7:26-33.
36.    Spilmont M, Leotoing L, Davicco MJ, Lebecque P, Miot-Noirault E, Pilet P, et al. Pomegranate Peel Extract Prevents Bone Loss in a Preclinical Model of Osteoporosis and Stimulates Osteoblastic Differentiation in vitro. Nutrients 2015;7:9265-9284.
37.    Shaban NZ, Talaat IM, Elrashidy FH, Hegazy AY, Sultan AS. Therapeutic role of Punica Granatum (Pomegranate) seed oil extract on bone turnover and resorption induced in ovariectomized rats. J Nutr Health Aging 2017;21:1299-1306.
38.    Yuniarti WM, Primarizky H, Lukiswanto BS. The activity of pomegranate extract standardized 40% ellagic acid during the healing process of incision wounds in albino rats (Rattus norvegicus). Vet World 2018;11:321-326.
39.    Beigi Boroujeni M, Shahrokhi SS, Birjandi M, Abbaszadeh A, Beyranvand F, Hamoleh S, et al. Effects of pomegranate peel extract on histopathology, testosterone levels and sperm of testicular torsion-detorsion induced in adult Wistar rats. J Complement Integr Med 2017;14.
40.    Wu S, Tian L. A new flavone glucoside together with known ellagitannins and flavones with anti-diabetic and anti-obesity activities from the flowers of pomegranate (Punica granatum). Nat Prod Res 2018:1-6.
41.    Wang L, Martins-Green M. Pomegranate and its components as alternative treatment for prostate cancer. Int J Mol Sci 2014;15:14949-14966.
42.    Wu TF, Hsu LT, Tsang BX, Huang LC, Shih WY, Chen LY. Clarification of the molecular pathway of Taiwan local pomegranate fruit juice underlying the inhibition of urinary bladder urothelial carcinoma cell by proteomics strategy. BMC Complement Altern Med 2016;16:96-105.
43.    Sturgeon SR, Ronnenberg AG. Pomegranate and breast cancer: possible mechanisms of prevention. Nutr Rev 2010;68:122-128.
44.    Tang J, Li B, Hong S, Liu C, Min J, Hu M, et al. Punicalagin suppresses the proliferation and invasion of cervical cancer cells through inhibition of the beta-catenin pathway. Mol Med Rep 2017;16:1439-1444.
45.    Banerjee N, Kim H, Talcott S, Mertens-Talcott S. Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR. Carcinogenesis 2013;34:2814-2822.
46.    Asmaa MJ, Ali AJ, Farid JM, Azman S. Growth inhibitory effects of crude pomegranate peel extract on chronic myeloid leukemia, K562 cells. Int J Appl Basic Med Res 2015;5:100-105.
47.    Bishayee A, Thoppil RJ, Darvesh AS, Ohanyan V, Meszaros JG, Bhatia D. Pomegranate phytoconstituents blunt the inflammatory cascade in a chemically induced rodent model of hepatocellular carcinogenesis. J Nutr Biochem 2013;24:178-187.
48.    Li Y, Yang F, Zheng W, Hu M, Wang J, Ma S, et al. Punica granatum (pomegranate) leaves extract induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in non-small cell lung cancer in vitro. Biomed Pharmacother 2016;80:227-235.
49.    Liu H, Zeng Z, Wang S, Li T, Mastriani E, Li QH, et al. Main components of pomegranate, ellagic acid and luteolin, inhibit metastasis of ovarian cancer by down-regulating MMP2 and MMP9. Cancer Biol Ther 2017;18:990-999.
50.    Nair V, Dai Z, Khan M, Ciolino HP. Pomegranate extract induces cell cycle arrest and alters cellular phenotype of human pancreatic cancer cells. Anticancer Res 2011;31:2699-2704.
51.    George J, Singh M, Srivastava AK, Bhui K, Shukla Y. Synergistic growth inhibition of mouse skin tumors by pomegranate fruit extract and diallyl sulfide: evidence for inhibition of activated MAPKs/NF-kappaB and reduced cell proliferation. Food Chem Toxicol 2011;49:1511-1520.
52.    Bagheri M, Fazli M, Saeednia S, Kor A, Ahmadiankia N. Pomegranate peel extract inhibits expression of beta-catenin, epithelial mesenchymal transition, and metastasis in triple negative breast cancer cells. Cell Mol Biol (Noisy-le-grand) 2018;64:86-91.
53.    Ahmadiankia N, Bagheri M, Fazli M. Gene expression changes in pomegranate peel extract-treated triple-negative breast cancer cells. Rep Biochem Mol Biol 2018;7:102-109.
54.    Costantini S, Rusolo F, De Vito V, Moccia S, Picariello G, Capone F, et al. Potential anti-inflammatory effects of the hydrophilic fraction of pomegranate (Punica granatum L.) seed oil on breast cancer cell lines. Molecules 2014;19:8644-8660.
55.    Rocha A, Wang L, Penichet M, Martins-Green M. Pomegranate juice and specific components inhibit cell and molecular processes critical for metastasis of breast cancer. Breast Cancer Res Treat 2012;136:647-658.
56.    Toi M, Bando H, Ramachandran C, Melnick SJ, Imai A, Fife RS, et al. Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis 2003;6:121-128.
57.    Adams LS, Seeram NP, Aggarwal BB, Takada Y, Sand D, Heber D. Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem 2006;54:980-985.
58.    Varghese S, Joseph MM, S RA, B SU, Sreelekha TT. The inhibitory effect of anti- tumor polysaccharide from Punica granatum on metastasis. Int J Biol Macromol 2017;103:1000-1010.
59.    Tang JM, Min J, Li BS, Hong SS, Liu C, Hu M, et al. Therapeutic effects of punicalagin against ovarian carcinoma cells in association with beta-catenin signaling inhibition. Int J Gynecol Cancer 2016;26:1557-1563.
60.    Rettig MB, Heber D, An J, Seeram NP, Rao JY, Liu H, et al. Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-kappaB-dependent mechanism. Mol Cancer Ther 2008;7:2662-2671.
61.    Sartippour MR, Seeram NP, Rao JY, Moro A, Harris DM, Henning SM, et al. Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo. Int J Oncol 2008;32:475-480.
62.    Wang L, Ho J, Glackin C, Martins-Green M. Specific pomegranate juice components as potential inhibitors of prostate cancer metastasis. Transl Oncol 2012;5:344-355.
63.    Pitchakarn P, Chewonarin T, Ogawa K, Suzuki S, Asamoto M, Takahashi S, et al. Ellagic acid inhibits migration and invasion by prostate cancer cell lines. Asian Pac J Cancer Prev 2013;14:2859-2863.
64.    Deng Y, Li Y, Yang F, Zeng A, Yang S, Luo Y, et al. The extract from Punica granatum (pomegranate) peel induces apoptosis and impairs metastasis in prostate cancer cells. Biomed Pharmacother 2017;93:976-984.
65.    Lansky EP, Harrison G, Froom P, Jiang WG. Pomegranate (Punica granatum) pure chemicals show possible synergistic inhibition of human PC-3 prostate cancer cell invasion across Matrigel. Invest New Drugs 2005;23:121-122.
66.    Lansky EP, Jiang W, Mo H, Bravo L, Froom P, Yu W, et al. Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest New Drugs 2005;23:11-20.
67.    An J, Guo Y, Wang T, Pantuck AJ, Rettig MB. Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-kappaB and JNK dependent manner. Asian J Urol 2015;2:38-45.
68.    Wells A, Grahovac J, Wheeler S, Ma B, Lauffenburger D. Targeting tumor cell motility as a strategy against invasion and metastasis. Trends Pharmacol Sci 2013;34:283-289.
69.    Guan X. Cancer metastases: challenges and opportunities. Acta Pharm Sin B 2015;5:402-418.
70.    Techasen A, Loilome W, Namwat N, Khuntikeo N, Puapairoj A, Jearanaikoon P, et al. Loss of E-cadherin promotes migration and invasion of cholangiocarcinoma cells and serves as a potential marker of metastasis. Tumour Biol 2014;35:8645-8652.
71.    Yeung KT, Yang J. Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol 2017;11:28-39.
72.    Guo F, Parker Kerrigan BC, Yang D, Hu L, Shmulevich I, Sood AK, et al. Post-transcriptional regulatory network of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions. J Hematol Oncol 2014;7:19.
73.    Song Y, Li J, Zhu Y, Dai Y, Zeng T, Liu L, et al. MicroRNA-9 promotes tumor metastasis via repressing E-cadherin in esophageal squamous cell carcinoma. Oncotarget 2014;5:11669-11680.
74.    Wang SC, Lin XL, Li J, Zhang TT, Wang HY, Shi JW, et al. MicroRNA-122 triggers mesenchymal-epithelial transition and suppresses hepatocellular carcinoma cell motility and invasion by targeting RhoA. PLoS One 2014;9:e101330.
75.    Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H. NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 2007;26:711-724.
76.    Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 2009;1:a001651.
77.    Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004;114:569-581.
78.    Pires BR, Mencalha AL, Ferreira GM, de Souza WF, Morgado-Diaz JA, Maia AM, et al. NF-kappaB is involved in the regulation of EMT genes in breast cancer cells. PLoS One 2017;12:e0169622.
79.    Kumar M, Allison DF, Baranova NN, Wamsley JJ, Katz AJ, Bekiranov S, et al. NF-kappaB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells. PLoS One 2013;8:e68597.
80.    Nicolson GL, Veljkovic V, Glisic S, Perovic V, Veljkovic N. Pomegranate (Punica granatum): A natural source for the development of therapeutic compositions of food supplements with anticancer activities based on electron acceptor molecular characteristics. Functional Foods in Health and Disease 2016;6:769-787.
81.    Martin TA. The role of tight junctions in cancer metastasis. Semin Cell Dev Biol 2014;36:224-231.
82.    Salvador E, Burek M, Forster CY. Tight junctions and the tumor microenvironment. Curr Pathobiol Rep 2016;4:135-145.
83.    Skubitz AP. Adhesion molecules. Cancer Treat Res 2002;107:305-329.
84.    Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A 2008;105:1516-1521.
85.    Rodrigues PC, Sawazaki-Calone I, Ervolino de Oliveira C, Soares Macedo CC, Dourado MR, Cervigne NK, et al. Fascin promotes migration and invasion and is a prognostic marker for oral squamous cell carcinoma. Oncotarget 2017;8:74736-74754.
86.    Yamamoto H, Kohashi K, Fujita A, Oda Y. Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor. Mod Pathol 2013;26:563-571.
87.    Das T, Bae YH, Wells A, Roy P. Profilin-1 overexpression upregulates PTEN and suppresses AKT activation in breast cancer cells. J Cell Physiol 2009;218:436-443.
88.    Piekny AJ, Glotzer M. Anillin is a scaffold protein that links RhoA, actin, and myosin during cytokinesis. Curr Biol 2008;18:30-36.
89.    Ohtsuka T, Nakanishi H, Ikeda W, Satoh A, Momose Y, Nishioka H, et al. Nexilin: a novel actin filament-binding protein localized at cell-matrix adherens junction. J Cell Biol 1998;143:1227-1238.
90.    Techasen A, Loilome W, Namwat N, Takahashi E, Sugihara E, Puapairoj A, et al. Myristoylated alanine-rich C kinase substrate phosphorylation promotes cholangiocarcinoma cell migration and metastasis via the protein kinase C-dependent pathway. Cancer Sci 2010;101:658-665.
91.    Hafeez BB, Zhong W, Weichert J, Dreckschmidt NE, Jamal MS, Verma AK. Genetic ablation of PKC epsilon inhibits prostate cancer development and metastasis in transgenic mouse model of prostate adenocarcinoma. Cancer Res 2011;71:2318-2327.
92.    Li T, Li D, Sha J, Sun P, Huang Y. MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochem Biophys Res Commun 2009;383:280-285.
93.    Gandellini P, Folini M, Longoni N, Pennati M, Binda M, Colecchia M, et al. miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res 2009;69:2287-2295.
94.    Kozma R, Ahmed S, Best A, Lim L. The GTPase-activating protein n-chimaerin cooperates with Rac1 and Cdc42Hs to induce the formation of lamellipodia and filopodia. Mol Cell Biol 1996;16:5069-5080.
95.    Mendez MG, Kojima S, Goldman RD. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. Faseb j 2010;24:1838-1851.
96.    Du L, Li J, Lei L, He H, Chen E, Dong J, et al. High vimentin expression predicts a poor prognosis and progression in colorectal cancer: A study with meta-analysis and TCGA database. Biomed Res Int 2018;2018:6387810.
97.    Kim YN, Koo KH, Sung JY, Yun UJ, Kim H. Anoikis resistance: an essential prerequisite for tumor metastasis. Int J Cell Biol 2012;2012:306879.
98.    Chung YC, Lu LC, Tsai MH, Chen YJ, Chen YY, Yao SP, et al. The inhibitory effect of ellagic Acid on cell growth of ovarian carcinoma cells. Evid Based Complement Alternat Med 2013;2013:306705.
99.    Mandal A, Bhatia D, Bishayee A. Anti-inflammatory mechanism involved in pomegranate-mediated prevention of breast cancer: the role of NF-kappaB and Nrf2 signaling pathways. Nutrients 2017;9.
100. Choi EM, Kwak SJ, Kim YM, Ha KS, Kim JI, Lee SW, et al. COX-2 inhibits anoikis by activation of the PI-3K/Akt pathway in human bladder cancer cells. Exp Mol Med 2005;37:199-203.
101. Zheng H, Li Y, Wang Y, Zhao H, Zhang J, Chai H, et al. Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion. Toxicol Appl Pharmacol 2014;280:10-20.
102. Roussos ET, Condeelis JS, Patsialou A. Chemotaxis in cancer. Nat Rev Cancer 2011;11:573-587.
103. Mishan MA, Ahmadiankia N, Bahrami AR. CXCR4 and CCR7: Two eligible targets in targeted cancer therapy. Cell Biol Int 2016;40:955-967.
104. Ahmadiankia N, Moghaddam HK, Mishan MA, Bahrami AR, Naderi-Meshkin H, Bidkhori HR, et al. Berberine suppresses migration of MCF-7 breast cancer cells through down-regulation of chemokine receptors. Iran J Basic Med Sci 2016;19:125-131.
105. Wang L, Li W, Lin M, Garcia M, Mulholland D, Lilly M, et al. Luteolin, ellagic acid and punicic acid are natural products that inhibit prostate cancer metastasis. Carcinogenesis 2014;35:2321-2330.
106. Guo M, Cai C, Zhao G, Qiu X, Zhao H, Ma Q, et al. Hypoxia promotes migration and induces CXCR4 expression via HIF-1alpha activation in human osteosarcoma. PLoS One 2014;9:e90518.
107. Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, et al. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 2006;86:1221-1232.
108. Liu J, Shen JX, Wu HT, Li XL, Wen XF, Du CW, et al. Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target. Discov Med 2018;25:211-223.
109. Shintani Y, Hollingsworth MA, Wheelock MJ, Johnson KR. Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res 2006;66:11745-11753.
110. Provenzano PP, Inman DR, Eliceiri KW, Keely PJ. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene 2009;28:4326-4343.
111. Kim SH, Lee HY, Jung SP, Kim S, Lee JE, Nam SJ, et al. Role of secreted type I collagen derived from stromal cells in two breast cancer cell lines. Oncol Lett 2014;8:507-512.
112. Jablonska-Trypuc A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem 2016;31:177-183.
113. Aslam MN, Lansky EP, Varani J. Pomegranate as a cosmeceutical source: pomegranate fractions promote proliferation and procollagen synthesis and inhibit matrix metalloproteinase-1 production in human skin cells. J Ethnopharmacol 2006;103:311-318.
114. Akhtar N, Khan NM, Ashruf OS, Haqqi TM. Inhibition of cartilage degradation and suppression of PGE2 and MMPs expression by pomegranate fruit extract in a model of posttraumatic osteoarthritis. Nutrition 2017;33:1-13.
115. Attiga FA, Fernandez PM, Weeraratna AT, Manyak MJ, Patierno SR. Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res 2000;60:4629-4637.
116. Larkins TL, Nowell M, Singh S, Sanford GL. Inhibition of cyclooxygenase-2 decreases breast cancer cell motility, invasion and matrix metalloproteinase expression. BMC Cancer 2006;6:181-192.
117. Shukla M, Gupta K, Rasheed Z, Khan KA, Haqqi TM. Bioavailable constituents/metabolites of pomegranate (Punica granatum L) preferentially inhibit COX2 activity ex vivo and IL-1beta-induced PGE2 production in human chondrocytes in vitro. J Inflamm (Lond) 2008;5:9-18.
118. Bourboulia D, Stetler-Stevenson WG. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin Cancer Biol 2010;20:161-168.
119. Wang W, Yang C, Wang XY, Zhou LY, Lao GJ, Liu D, et al. MicroRNA-129 and -335 promote diabetic wound healing by inhibiting Sp1-Mediated MMP-9 expression. Diabetes 2018;67:1627-1638.
120. Roy S, Khanna S, Hussain SR, Biswas S, Azad A, Rink C, et al. MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. Cardiovasc Res 2009;82:21-29.
121. Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS, et al. MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 2008;28:5369-5380.
122. Mele V, Sokol L, Kolzer VH, Pfaff D, Muraro MG, Keller I, et al. The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer. Oncotarget 2017;8:70617-70629.
123. Turley EA, Noble PW, Bourguignon LY. Signaling properties of hyaluronan receptors. J Biol Chem 2002;277:4589-4592.
124. Cheng XB, Sato N, Kohi S, Koga A, Hirata K. Receptor for hyaluronic acid-mediated motility is associated with poor survival in pancreatic ductal adenocarcinoma. J Cancer 2015;6:1093-1098.
125. Paron I, Berchtold S, Voros J, Shamarla M, Erkan M, Hofler H, et al. Tenascin-C enhances pancreatic cancer cell growth and motility and affects cell adhesion through activation of the integrin pathway. PLoS One 2011;6:e21684.
126. Midwood KS, Orend G. The role of tenascin-C in tissue injury and tumorigenesis. J Cell Commun Signal 2009;3:287-310.
127. Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 2008;451:147-152.
128. Wang L, Alcon A, Yuan H, Ho J, Li QJ, Martins-Green M. Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. Integr Biol (Camb) 2011;3:742-754.
129. Wu Y, Zhou BP. Inflammation: a driving force speeds cancer metastasis. Cell Cycle 2009;8:3267-3273.
130. Rahimi HR, Arastoo M, Ostad SN. A comprehensive review of Punica granatum (Pomegranate) properties in toxicological, pharmacological, cellular and molecular biology researches. Iran J Pharm Res 2012;11:385-400.