{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:02:25Z","timestamp":1785438145263,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006545","name":"Institutes of Health","doi-asserted-by":"publisher","award":["1SC1GM121202"],"award-info":[{"award-number":["1SC1GM121202"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"Institutes of Health","doi-asserted-by":"publisher","award":["1R35GM149318"],"award-info":[{"award-number":["1R35GM149318"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"Institutes of Health","doi-asserted-by":"publisher","award":["U54MD007598"],"award-info":[{"award-number":["U54MD007598"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1SC1GM121202"],"award-info":[{"award-number":["1SC1GM121202"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R35GM149318"],"award-info":[{"award-number":["1R35GM149318"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U54MD007598"],"award-info":[{"award-number":["U54MD007598"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Obesity is associated with aggressive prostate cancer, but the links between metabolic dysregulation, inflammation, adipocyte-associated signaling, and tumor growth remain incompletely defined. This study examined whether high-fat diet (HFD)-associated systemic changes and adipocyte-derived paracrine interactions are linked to prostate cancer growth in preclinical models. Methods: An HFD xenograft model and adipocyte co-culture systems were used to evaluate systemic and local tumor-supportive features. Pharmacologic\/nutritional modulation was tested using green tea or EGCG, arctigenin, and the CCR2 antagonist RS 504393, alone or in combination. Tumor growth, cell proliferation, angiogenesis-related features, circulating metabolic and cytokine levels, and selected tumor-associated signaling proteins were analyzed. Results: HFD feeding was associated with increased circulating free fatty acids, IGF-1, MCP-1, IL-6, and VEGF, together with increased tumor growth, Ki67 staining, and CD31-positive microvessel density. Adipocyte co-culture systems were used to evaluate treatment-associated changes in prostate cancer cell proliferation under adipocyte-associated conditions. Combined modulation with green tea\/EGCG, arctigenin, and RS 504393 was associated with greater reductions in adipocyte-associated proliferation, tumor growth, Ki67 staining, and CD31-positive microvessel density than single or dual interventions. Antibody array analysis showed treatment-associated changes in selected stress- and apoptosis-related proteins, including cleaved caspase-7 and phosphorylated Chk1. Conclusions: HFD-associated metabolic and inflammatory alterations, adipocyte-associated interactions, proliferative activity, angiogenesis-related features, and stress\/apoptosis-related signaling changes were linked within a tumor-supportive framework in preclinical prostate cancer models. Combined pharmacologic\/nutritional modulation was associated with reduced tumor-supportive features under HFD conditions. Further mechanistic and translational validation is needed.<\/jats:p>","DOI":"10.3390\/biom16070969","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T12:41:38Z","timestamp":1782909698000},"page":"969","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combined Pharmacologic and Nutritional Modulation of High-Fat Diet-Associated Tumor-Supportive Features in Prostate Cancer Models"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7195-9601","authenticated-orcid":false,"given":"Ke","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Cancer Research and Training, Institute for Advanced Biomedical Research, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4720-767X","authenticated-orcid":false,"given":"Qiongyu","family":"Hao","sequence":"additional","affiliation":[{"name":"Division of Cancer Research and Training, Institute for Advanced Biomedical Research, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5900-1644","authenticated-orcid":false,"given":"Joshua","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Cancer Research and Training, Institute for Advanced Biomedical Research, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahya","family":"Elshimali","sequence":"additional","affiliation":[{"name":"Division of Cancer Research and Training, Institute for Advanced Biomedical Research, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara E.","family":"Magyar","sequence":"additional","affiliation":[{"name":"Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne M.","family":"Henning","sequence":"additional","affiliation":[{"name":"Center for Human Nutrition, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Andalibi","sequence":"additional","affiliation":[{"name":"Division of Cancer Research and Training, Institute for Advanced Biomedical Research, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Cancer Research and Training, Institute for Advanced Biomedical Research, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1016\/S0140-6736(24)00651-2","article-title":"The Lancet Commission on prostate cancer: Planning for the surge in cases","volume":"403","author":"James","year":"2024","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/S0140-6736(21)00950-8","article-title":"Prostate cancer","volume":"398","author":"Sandhu","year":"2021","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/s41419-022-05084-1","article-title":"Second generation androgen receptor antagonists and challenges in prostate cancer treatment","volume":"13","author":"Chen","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7675","DOI":"10.1038\/s41467-024-52032-y","article-title":"Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells","volume":"15","author":"Safi","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3883","DOI":"10.1038\/s41388-025-03573-z","article-title":"Evolving roles for the androgen receptor and its protein interactome in castration-resistant prostate cancer","volume":"44","author":"Chukhu","year":"2025","journal-title":"Oncogene"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.1038\/s41388-024-03175-1","article-title":"Stromal androgen signaling governs essential niches in supporting prostate development and tumorigenesis","volume":"43","author":"Rhee","year":"2024","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/s41585-023-00764-9","article-title":"Obesity and prostate cancer\u2014Microenvironmental roles of adipose tissue","volume":"20","author":"Saha","year":"2023","journal-title":"Nat. Rev. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rivera-Izquierdo, M., P\u00e9rez de Rojas, J., Mart\u00ednez-Ruiz, V., P\u00e9rez-G\u00f3mez, B., S\u00e1nchez, M.J., Khan, K.S., and Jim\u00e9nez-Mole\u00f3n, J.J. (2021). Obesity as a Risk Factor for Prostate Cancer Mortality: A Systematic Review and Dose-Response Meta-Analysis of 280,199 Patients. Cancers, 13.","DOI":"10.3390\/cancers13164169"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/s41568-024-00743-1","article-title":"Macrophages and T cells in metabolic disorder-associated cancers","volume":"24","author":"Taranto","year":"2024","journal-title":"Nat. Rev. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41574-024-01032-5","article-title":"The multifactorial effect of obesity on the effectiveness and outcomes of cancer therapies","volume":"20","author":"Lysaght","year":"2024","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/s41574-023-00932-2","article-title":"Emerging mechanisms of obesity-associated immune dysfunction","volume":"20","author":"Shaikh","year":"2024","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1038\/s41416-024-02762-z","article-title":"Metabolic adaptations in prostate cancer","volume":"131","author":"Carracedo","year":"2024","journal-title":"Br. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41568-024-00786-4","article-title":"Metabolic interplays between the tumour and the host shape the tumour macroenvironment","volume":"25","author":"Janowitz","year":"2025","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1038\/s41416-021-01435-5","article-title":"Metabolic reprogramming in prostate cancer","volume":"125","author":"Ahmad","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1038\/s41556-023-01298-3","article-title":"Metabolically regulated lineages in prostate cancer","volume":"25","author":"Bakht","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4052","DOI":"10.1038\/s41467-024-48179-3","article-title":"Dysfunctional adipocytes promote tumor progression through YAP\/TAZ-dependent cancer-associated adipocyte transformation","volume":"15","author":"Song","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_19","first-page":"456","article-title":"Metabolic alterations drive enzalutamide resistance","volume":"20","author":"Masone","year":"2023","journal-title":"Nat. Rev. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/s41391-024-00886-0","article-title":"Cardiovascular events among men with prostate cancer treated with androgen receptor signaling inhibitors: A systematic review, meta-analysis, and network meta-analysis","volume":"28","author":"Matsukawa","year":"2025","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1038\/s41556-023-01274-x","article-title":"Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment","volume":"25","author":"Giafaglione","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sacca, P.A., and Calvo, J.C. (2022). Periprostatic Adipose Tissue Microenvironment: Metabolic and Hormonal Pathways During Prostate Cancer Progression. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.863027"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"20896","DOI":"10.1038\/s41598-024-71862-w","article-title":"MRI-measured periprostatic to subcutaneous adipose tissue thickness ratio as an independent risk factor in prostate cancer patients undergoing radical prostatectomy","volume":"14","author":"Jiang","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1089\/end.2023.0215","article-title":"Periprostatic Adipose Tissue MRI Radiomics-Derived Features Associated with Clinically Significant Prostate Cancer","volume":"37","author":"Shahait","year":"2023","journal-title":"J. Endourol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s12964-024-01474-4","article-title":"Adipo-oncology: Adipocyte-derived factors govern engraftment, survival, and progression of metastatic cancers","volume":"22","author":"Sato","year":"2024","journal-title":"Cell Commun. Signal. CCS"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/s41419-026-08577-5","article-title":"A feedback mechanism from prostate cancer cells to macrophages, reinforced by STAT1, regulates tumor progression and resistance to radiotherapy","volume":"17","author":"Chen","year":"2026","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115334","DOI":"10.1016\/j.bcp.2022.115334","article-title":"MCP-1 facilitates VEGF production by removing miR-374b-5p blocking of VEGF mRNA translation","volume":"206","author":"Zhao","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s10654-021-00838-1","article-title":"Longitudinal trajectories of lifetime body shape and prostate cancer angiogenesis","volume":"37","author":"Wang","year":"2022","journal-title":"Eur. J. Epidemiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12929-022-00796-0","article-title":"The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy","volume":"29","author":"Duarte","year":"2022","journal-title":"J. Biomed. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Xiao, Y., Tang, B., Wang, J., Cai, Z., An, H., and Tao, N. (2025). Study of the interaction between cardiometabolic index and inflammatory index on the risk of prostate cancer development. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1591879"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Trecarten, S., Liss, M.A., Hamilton-Reeves, J., and DiGiovanni, J. (2025). Obesity, dietary interventions and microbiome alterations in the development and progression of prostate cancer. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1448116"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.1016\/j.apsb.2025.04.029","article-title":"Obesity-cancer axis crosstalk: Molecular insights and therapeutic approaches","volume":"15","author":"Rakib","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Altinoz, H.B., and Sanlier, N. (2026). Green tea catechins and prostate cancer: Mechanisms, clinical evidence, and safety: A narrative review. BMC Cancer, 26.","DOI":"10.1186\/s12885-025-15516-8"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Bai, B., Chen, Q., Jing, R., He, X., Wang, H., Ban, Y., Ye, Q., Xu, W., and Zheng, C. (2021). Molecular Basis of Prostate Cancer and Natural Products as Potential Chemotherapeutic and Chemopreventive Agents. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.738235"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4114","DOI":"10.1039\/D0FO00565G","article-title":"Prospective randomized trial evaluating blood and prostate tissue concentrations of green tea polyphenols and quercetin in men with prostate cancer","volume":"11","author":"Henning","year":"2020","journal-title":"Food Funct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jnutbio.2013.09.005","article-title":"Enhanced inhibition of prostate cancer xenograft tumor growth by combining quercetin and green tea","volume":"25","author":"Wang","year":"2014","journal-title":"J. Nutr. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kadomoto, S., Izumi, K., and Mizokami, A. (2021). Roles of CCL2-CCR2 Axis in the Tumor Microenvironment. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168530"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1093\/carcin\/21.11.2035","article-title":"Effect of black and green tea polyphenols on c-jun phosphorylation and H2O2 production in transformed and non-transformed human bronchial cell lines. possible mechanisms of cell growth inhibition and apoptosis induction","volume":"21","author":"Yang","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1038\/s41598-020-58354-3","article-title":"Arctigenin inhibits prostate tumor growth in high-fat diet fed mice through dual actions on adipose tissue and tumor","volume":"10","author":"Hao","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1007\/s11154-023-09838-w","article-title":"Exploring the role of the inflammasomes on prostate cancer: Interplay with obesity","volume":"24","author":"Gahete","year":"2023","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Fontana, F., Anselmi, M., Carollo, E., Sartori, P., Procacci, P., Carter, D., and Limonta, P. (2022). Adipocyte-Derived Extracellular Vesicles Promote Prostate Cancer Cell Aggressiveness by Enabling Multiple Phenotypic and Metabolic Changes. Cells, 11.","DOI":"10.3390\/cells11152388"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5321","DOI":"10.62347\/AHQT5920","article-title":"Effect of subcutaneous adipose tissue-associated CSRP2 on the progression of prostate cancer via the WDR5\/USP44 pathway","volume":"14","author":"Wang","year":"2024","journal-title":"Am. J. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7732","DOI":"10.1021\/jf071303g","article-title":"Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland","volume":"55","author":"Seeram","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4270","DOI":"10.1200\/JCO.2016.67.4283","article-title":"Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation","volume":"34","author":"Iyengar","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pepe, L., Pizzimenti, C., Tralongo, P., Zuccal\u00e0, V., Ieni, A., Pepe, P., Ricciardi, G., Cianci, V., Mondello, C., and Martini, M. (2026). PD-L1 Expression in Prostate Cancer: Anatomopathological Features, Methodological Pitfalls, and Therapeutic Potential. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27041797"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cell.2015.08.068","article-title":"Preclinical mouse cancer models: A maze of opportunities and challenges","volume":"163","author":"Day","year":"2015","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1158\/2159-8290.CD-18-0044","article-title":"Mouse Models for Cancer Immunotherapy Research","volume":"8","author":"Olson","year":"2018","journal-title":"Cancer Discov."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/7\/969\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T14:43:56Z","timestamp":1782917036000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/7\/969"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":47,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["biom16070969"],"URL":"https:\/\/doi.org\/10.3390\/biom16070969","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]}}}