{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:18:31Z","timestamp":1788542311885,"version":"build-2803163510"},"reference-count":62,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T00:00:00Z","timestamp":1649721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006545","name":"NIMHD","doi-asserted-by":"publisher","award":["U54MD007590"],"award-info":[{"award-number":["U54MD007590"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R25G06414"],"award-info":[{"award-number":["R25G06414"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Prostate cancer development and progression are associated with increased infiltrating macrophages. Prostate cancer is derived from prostatic intraepithelial neoplasia (PIN) lesions. However, the effects macrophages have on PIN progression remain unclear. Here, we showed that the recruited macrophages adjacent to PIN expressed M2 macrophage markers. In addition, high levels of Spp1 transcripts, also known as osteopontin, were identified in these macrophages. Extraneously added Spp1 accelerated PIN cell proliferation through activation of Akt and JNK in a 3D culture setting. We also showed that PIN cells expressed CD44, integrin \u03b1v, integrin \u03b21, and integrin \u03b23, all of which have been previously reported as receptors for Spp1. Finally, blockade of Akt and JNK activation through their specific inhibitor completely abolished macrophage Spp1-induced cell proliferation of PIN. Hence, our data revealed Spp1 as another macrophage cytokine\/growth factor and its mediated mechanism to upregulate PIN cell growth, thus promoting prostate cancer development.<\/jats:p>","DOI":"10.3390\/ijms23084247","type":"journal-article","created":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T02:48:59Z","timestamp":1649731739000},"page":"4247","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Macrophages Cytokine Spp1 Increases Growth of Prostate Intraepithelial Neoplasia to Promote Prostate Tumor Progression"],"prefix":"10.3390","volume":"23","author":[{"given":"Justin K.","family":"Messex","sequence":"first","affiliation":[{"name":"Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal J.","family":"Byrd","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikalah U.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2728-3752","authenticated-orcid":false,"given":"Geou-Yarh","family":"Liou","sequence":"additional","affiliation":[{"name":"Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA"},{"name":"Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.15585\/mmwr.mm6941a1","article-title":"Prostate cancer incidence and surivival, by stae and race\/ethnicity-United States, 2001\u20132017","volume":"69","author":"Siegel","year":"2020","journal-title":"Morb. Mortal. Wkly. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1001\/jama.1997.03540300035030","article-title":"Fifteen-year surivival in prostate cancer. A prospective, population-based study in Sweden","volume":"277","author":"Johansson","year":"1997","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2119568","DOI":"10.1001\/jamanetworkopen.2021.19568","article-title":"Causes of death among patients with metastatic prostate cancer in the US from 2000 to 2016","volume":"4","author":"Elmehrath","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7718","DOI":"10.1038\/s41598-018-26143-8","article-title":"Macrophage Cytokines Enhance Cell Proliferation of Normal Prostate Epithelial Cells through Activation of ERK and Akt","volume":"8","author":"Dang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1365-2559.2011.04033.x","article-title":"Prostate cancer and inflammation: The evidence","volume":"60","author":"Sfanos","year":"2012","journal-title":"Histopathology"},{"key":"ref_6","first-page":"455","article-title":"Inflammation in prostate cancer progression and therapeutic targeting","volume":"4","author":"Stark","year":"2015","journal-title":"Transl. Androl. Urol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1111\/febs.15541","article-title":"Macrophages expedite cell proliferation of prostate intraepithelial neoplasia through their downstream target ERK","volume":"288","author":"Thomas","year":"2021","journal-title":"FEBS J."},{"key":"ref_8","first-page":"491","article-title":"Macrophage cytokines: Involvement in immunity and infectious diseases","volume":"5","author":"Descoteaux","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"281","DOI":"10.2174\/1568010054022024","article-title":"Macrophages in inflammation","volume":"4","author":"Fujiwara","year":"2005","journal-title":"Curr. Drug Targets Inflamm. Allergy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/ni.1937","article-title":"Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm","volume":"11","author":"Biswas","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.semcancer.2008.03.004","article-title":"Macrophage polarization in tumour progression","volume":"18","author":"Sica","year":"2008","journal-title":"Semin. Cancer Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"816460","DOI":"10.1155\/2015\/816460","article-title":"Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms","volume":"2015","author":"Roszer","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1002\/pros.23742","article-title":"M2 macrophages and regulatory T cells in lethal prostate cancer","volume":"79","author":"Erlandsson","year":"2019","journal-title":"Prostate"},{"key":"ref_14","first-page":"523","article-title":"Association between tumor-associated macrophage infiltration, high grade prostate cancer, and biochemical recurrence after radical prostatectomy","volume":"3","author":"Gollapudi","year":"2013","journal-title":"Am. J. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"486798","DOI":"10.1155\/2014\/486798","article-title":"The role of M1 and M2 macrophages in prostate cancer in relation to extracapsular tumor extension and biochemical recurrence after radical prostatectomy","volume":"2014","author":"Lanciotti","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_16","first-page":"445","article-title":"Tumor associated macrophages in human prostate cancer: Relation to clinicopathological variables and survival","volume":"17","author":"Lissbrant","year":"2000","journal-title":"Int. J. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3389\/fendo.2018.00247","article-title":"Multifaceted Roles for Macrophages in Prostate Cancer Skeletal Metastasis","volume":"9","author":"Lo","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15651","DOI":"10.1038\/srep15651","article-title":"Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions","volume":"5","author":"Lundholm","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1111\/j.1464-410X.2010.09804.x","article-title":"Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer","volume":"107","author":"Nonomura","year":"2011","journal-title":"BJU Int."},{"key":"ref_20","first-page":"420","article-title":"Metabolic reprograming in macrophage polarization","volume":"5","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.3389\/fimmu.2018.01593","article-title":"CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions","volume":"9","author":"Amici","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Jablonski, K.A., Amici, S.A., Webb, L.M., Ruiz-Rosado Jde, D., Popovich, P.G., Partida-Sanchez, S., and Guerau-de-Arellano, M. (2015). Novel Markers to Delineate Murine M1 and M2 Macrophages. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145342"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1038\/sj.onc.1204436","article-title":"Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms","volume":"20","author":"Belmokhtar","year":"2001","journal-title":"Oncogene"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1136\/bjo.87.3.346","article-title":"Mechanisms of staurosporine induced apoptosis in a human corneal endothelial cell line","volume":"87","author":"Thuret","year":"2003","journal-title":"Br. J. Ophthalmol."},{"key":"ref_25","first-page":"219","article-title":"CD44 variants but not CD44s cooperate with beta1-containing integrins to permit cells to bind to osteopontin independently of arginine-glycine-aspartic acid, thereby stimulating cell motility and chemotaxis","volume":"59","author":"Katagiri","year":"1999","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1126\/science.271.5248.509","article-title":"Receptor-ligand interaction between CD44 and osteopontin (Eta-1)","volume":"271","author":"Weber","year":"1996","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1242\/jcs.111.9.1165","article-title":"Osteopontin is a ligand for the alpha4beta1 integrin","volume":"111","author":"Bayless","year":"1998","journal-title":"J. Cell Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"26232","DOI":"10.1074\/jbc.270.44.26232","article-title":"A biochemical characterization of the binding of osteopontin to integrins alpha v beta 1 and alpha v beta 5","volume":"270","author":"Hu","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1006\/excr.1998.4108","article-title":"Structural requirements for alpha 9 beta 1-mediated adhesion and migration to thrombin-cleaved osteopontin","volume":"242","author":"Smith","year":"1998","journal-title":"Exp. Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/sj.cr.7290105","article-title":"MAPK signal pathways in the regulation of cell proliferation in mammalian cells","volume":"12","author":"Zhang","year":"2002","journal-title":"Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/sj.leu.2402824","article-title":"Involvement of PI3K\/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy","volume":"17","author":"Chang","year":"2003","journal-title":"Leukemia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S1535-6108(03)00248-4","article-title":"Targeting the PI3K-Akt pathway in human cancer: Rationale and promise","volume":"4","author":"Luo","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1210\/endo.137.6.8641196","article-title":"Osteopontin activation of c-src in human melanoma cells requires the cytoplasmic domain of the integrin alpha v-subunit","volume":"137","author":"Chellaiah","year":"1996","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11051","DOI":"10.1074\/jbc.M310256200","article-title":"Osteopontin induces AP-1-mediated secretion of urokinase-type plasminogen activator through c-Src-dependent epidermal growth factor receptor transactivation in breast cancer cells","volume":"279","author":"Das","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14487","DOI":"10.1074\/jbc.M207309200","article-title":"Osteopontin induces nuclear factor kappa B-mediated promatrix metalloproteinase-2 activation through I kappa B alpha \/IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways","volume":"278","author":"Philip","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.3390\/cancers6031670","article-title":"Tumor-associated macrophages as major players in the tumor microenvironment","volume":"6","author":"Chanmee","year":"2014","journal-title":"Cancers"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature01322","article-title":"Inflammation and cancer","volume":"420","author":"Coussens","year":"2002","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.it.2011.12.001","article-title":"Differential macrophage programming in the tumor microenvironment","volume":"33","author":"Ruffell","year":"2012","journal-title":"Trends Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kasprzak, A., and Szaflarski, W. (2020). Role of alternatively spliced messager RNA (mRNA) isoformas of insulin-like growth factor 1 (IGF1) in selected human tumors. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21196995"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1093\/jnci\/94.7.513","article-title":"Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling","volume":"94","author":"Agrawal","year":"2002","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1038\/sj.bjc.6601839","article-title":"Role of osteopontin in tumour progression","volume":"90","author":"Rittling","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1158\/1055-9965.EPI-06-1008","article-title":"The role of osteopontin in tumor progression and metastasis in breast cancer","volume":"16","author":"Rodrigues","year":"2007","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_43","first-page":"2271","article-title":"Osteopontin: Possible role in prostate cancer progression","volume":"5","author":"Thalmann","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"633","DOI":"10.3892\/mco.2015.517","article-title":"Prognostic significance of osteopontin expression in non-small-cell lung cancer: A meta-analysis","volume":"3","author":"Zou","year":"2015","journal-title":"Mol. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1158\/0008-5472.CAN-05-2816","article-title":"Increased expression of osteopontin contributes to the progression of prostate cancer","volume":"66","author":"Khodavirdi","year":"2006","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1002\/ijc.21619","article-title":"Prognostic significance of osteopontin expression in human prostate cancer","volume":"118","author":"Forootan","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_47","first-page":"2329","article-title":"Methylation of the CD44 metastasis suppressor gene in human prostate cancer","volume":"59","author":"Lou","year":"1999","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1038\/labinvest.3780137","article-title":"Silencing of CD44 expression in prostate cancer by hypermethylation of the CD44 promoter region","volume":"80","author":"Verkaik","year":"2000","journal-title":"Lab. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1093\/ajcp\/106.5.647","article-title":"Altered expression of CD44 in human prostate cancer during progression","volume":"106","author":"Nagabhushan","year":"1996","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0304-3835(98)00088-3","article-title":"Relationship between CD44 expression and differentiation of human prostate adenocarcinomas","volume":"129","author":"Takahashi","year":"1998","journal-title":"Cancer Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1006\/bbrc.1999.2032","article-title":"A regulated interaction between alpha5beta1 integrin and osteopontin","volume":"267","author":"Barry","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.matbio.2005.05.005","article-title":"Distinct structural requirements for binding of the integrins alphavbeta6, alphavbeta3, alphavbeta5, alpha5beta1 and alpha9beta1 to osteopontin","volume":"24","author":"Yokosaki","year":"2005","journal-title":"Matrix Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1091\/mbc.9.6.1425","article-title":"Identification of osteopontin as a novel ligand for the integrin alpha8 beta1 and potential roles for this integrin-ligand interaction in kidney morphogenesis","volume":"9","author":"Denda","year":"1998","journal-title":"Mol. Biol. Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0014-5793(01)02690-4","article-title":"Structural elements of the osteopontin SVVYGLR motif important for the interaction with alpha(4) integrins","volume":"503","author":"Green","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6238","DOI":"10.1038\/sj.onc.1210429","article-title":"Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling","volume":"26","author":"McCabe","year":"2007","journal-title":"Oncogene"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s10637-017-0433-4","article-title":"ProCAID: A phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer","volume":"35","author":"Crabb","year":"2017","journal-title":"Investig. New Drugs"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1158\/1078-0432.CCR-18-0981","article-title":"Randomized phase II study evaluating Akt blockade with Ipatasertibe, in combination with Abiraerone, in patients with metastatic prostate cancer with and without PTEN loss","volume":"25","author":"Rodrigues","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8230","DOI":"10.1073\/pnas.1120508109","article-title":"Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery","volume":"109","author":"Karve","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"8976","DOI":"10.1021\/acsnano.5b02913","article-title":"Improving cancer chemoradiotherapy treatment by dual controlled release of wortmannin and docetaxel in polymeric nanoparticles","volume":"9","author":"Au","year":"2015","journal-title":"ACS Nano"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"109679","DOI":"10.1016\/j.biopha.2019.109679","article-title":"The role of JNK in prostate cancer progression and therapeutic strategies","volume":"121","author":"Xu","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1016\/j.chembiol.2014.09.007","article-title":"Recent progress in the design, study, and development of c-Jun N-tterminal kinase inhibitors as anticancer agents","volume":"21","author":"Messoussi","year":"2014","journal-title":"Chem. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/sj.neo.7900210","article-title":"Development of PIN and prostate adenocarcinoma cell lines: A model system for multistage tumor progression","volume":"4","author":"Soares","year":"2002","journal-title":"Neoplasia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/8\/4247\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:52:09Z","timestamp":1760136729000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/8\/4247"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,12]]},"references-count":62,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23084247"],"URL":"https:\/\/doi.org\/10.3390\/ijms23084247","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,12]]}}}