{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:50:23Z","timestamp":1760241023198,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T00:00:00Z","timestamp":1573430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research from JSPS","award":["JP19H03597"],"award-info":[{"award-number":["JP19H03597"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Significant numbers of malignant tumor cells that have spread to surrounding tissues and other distant organs are often too small to be picked up in a diagnostic test, and prevention of even such small metastases should improve patient outcomes. Using a mouse model, we show in this article that intravenous administration of a human CCL3 variant carrying a single amino acid substitution after mild local hyperthermia not only induces tumor growth inhibition at the treated site but also inhibits metastasis. Colon26 adenocarcinoma cells (1 \u00d7 105 cells\/mouse) were grafted subcutaneously into the right hind leg of syngeneic BALB\/c mice and after nine days, when tumor size reached ~11 mm in diameter, the local tumor mass was exposed to high-frequency waves, by which intratumoral temperature was maintained at 42 \u00b0C for 30 min. Mice received the CCL3 variant named eMIP (2 \u03bcg\/mouse\/day) intravenously for five consecutive days starting one day after heat treatment. We found that tumor growth in eMIP recipients after hyperthermia was inhibited markedly but no effect was seen in animals treated with either hyperthermia or eMIP alone. Furthermore, the number of lung metastases evaluated at 18 days after hyperthermia treatment was dramatically reduced in animals receiving the combination therapy compared with all other controls. These results encourage future clinical application of this combination therapy.<\/jats:p>","DOI":"10.3390\/cancers11111770","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T04:07:07Z","timestamp":1573531627000},"page":"1770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Anti-Metastatic Benefits Produced by Hyperthermia and a CCL3 Derivative"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6597-6061","authenticated-orcid":false,"given":"Liqiu","family":"Ma","sequence":"first","affiliation":[{"name":"Gunma University Heavy Ion Medical Center, Gunma 371-8511, Japan"},{"name":"China Institute of Atomic Energy, Beijing 102413, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryosuke","family":"Kambe","sequence":"additional","affiliation":[{"name":"Gunma University Heavy Ion Medical Center, Gunma 371-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoko","family":"Tsuchiya","sequence":"additional","affiliation":[{"name":"Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7867-0109","authenticated-orcid":false,"given":"Shiro","family":"Kanegasaki","sequence":"additional","affiliation":[{"name":"Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9960-2153","authenticated-orcid":false,"given":"Akihisa","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Gunma University Heavy Ion Medical Center, Gunma 371-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/02656730150201552","article-title":"Hyperthermia in oncology","volume":"17","author":"Falk","year":"2001","journal-title":"Int. J. Hyperth."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Oldenborg, S., van Os, R., Oei, B., and Poortmans, P. (2019). Impact of technique and schedule of reirradiation plus hyperthermia on outcome after surgery for patients with recurrent breast cancer. Cancers (Basel), 11.","DOI":"10.3390\/cancers11060782"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Helderman, R., Loke, D.R., Kok, H.P., Oei, A.L., Tanis, P.J., Franken, N., and Crezee, J. (2019). Variation in clinical application of hyperthermic intraperitoneal chemotherapy: A review. Cancers (Basel), 11.","DOI":"10.3390\/cancers11010078"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3799","DOI":"10.3390\/cancers3043799","article-title":"Combined hyperthermia and radiotherapy for the treatment of cancer","volume":"3","author":"Kaur","year":"2011","journal-title":"Cancers (Basel)"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1006\/bbrc.1999.1637","article-title":"Heat shock suppresses membrane type 1-matrix metalloproteinase production and progelatinase A activation in human fibrosarcoma HT-1080 cells and thereby inhibits cellular invasion","volume":"265","author":"Sato","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mahmood, J., Shukla, H.D., Soman, S., Samanta, S., Singh, P., Kamlapurkar, S., Saeed, A., Amin, N.P., and Vujaskovic, Z. (2018). Immunotherapy, radiotherapy, and hyperthermia: A combined therapeutic approach in pancreatic cancer treatment. Cancers (Basel), 10.","DOI":"10.3390\/cancers10120469"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s13566-015-0219-2","article-title":"Predictors of clinical response to immunotherapy with or without radiotherapy","volume":"4","author":"Hiniker","year":"2015","journal-title":"J. Radiat. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nrc.2016.16","article-title":"Vaccines for established cancer: Overcoming the challenges posed by immune evasion","volume":"16","author":"Arens","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4108","DOI":"10.1182\/blood-2002-05-1389","article-title":"Stressed apoptotic tumor cells stimulate dendritic cells and induce specific cytotoxic T cells","volume":"100","author":"Feng","year":"2002","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"528","DOI":"10.3109\/02656736.2012.677933","article-title":"Old and new facts about hyperthermia-induced modulations of the immune system","volume":"28","author":"Frey","year":"2012","journal-title":"Int. J. Hyperth."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tsang, Y.W., Huang, C.C., Yang, K.L., Chi, M.S., Chiang, H.C., Wang, Y.S., Andocs, G., Szasz, A., Li, W.T., and Chi, K.H. (2015). Improving immunological tumor microenvironment using electro-hyperthermia followed by dendritic cell immunotherapy. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1690-2"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1158\/1078-0432.CCR-07-4485","article-title":"Enhancement of antitumor radiation efficacy and consistent induction of the abscopal effect in mice by ECI301, an active variant of macrophage inflammatory protein-1alpha","volume":"14","author":"Shiraishi","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.1158\/0008-5472.CAN-14-0551","article-title":"Macrophage inflammatory protein derivative ECI301 enhances the alarmin-associated abscopal benefits of tumor radiotherapy","volume":"74","author":"Kanegasaki","year":"2014","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e1311433","DOI":"10.1080\/2162402X.2017.1311433","article-title":"Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells","volume":"6","author":"Adkins","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/S0140-6736(96)91015-6","article-title":"The war on cancer","volume":"347","author":"Sporn","year":"1996","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"695","DOI":"10.3892\/or.2016.5300","article-title":"Chemoradiotherapy and concurrent radiofrequency thermal therapy to treat primary rectal cancer and prediction of treatment responses","volume":"37","author":"Shoji","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.colsurfb.2018.10.051","article-title":"Recent advances in magnetic fluid hyperthermia for cancer therapy","volume":"174","author":"Das","year":"2019","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_19","first-page":"1","article-title":"Application of heat to cancer chemotherapy--experimental studies","volume":"30","author":"Suzuki","year":"1967","journal-title":"Nagoya J. Med. Sci."},{"key":"ref_20","first-page":"1263","article-title":"In vitro-in vivo studies on the susceptibility of the solid Yoshida sarcoma to drugs and hyperthermia (42 degrees)","volume":"34","author":"Dickson","year":"1974","journal-title":"Cancer Res."},{"key":"ref_21","first-page":"1165","article-title":"In vitro thermochemotherapy of human colon cancer cells with cis-dichlorodiammineplatinum(II) and mitomycin C","volume":"40","author":"Barlogie","year":"1980","journal-title":"Cancer Res."},{"key":"ref_22","first-page":"4014","article-title":"Sensitivity of xenografts of human pancreatic adenocarcinoma in nude mice to heat and heat combined with chemotherapy","volume":"43","author":"Shiu","year":"1983","journal-title":"Cancer Res."},{"key":"ref_23","first-page":"3977","article-title":"Enhancement of antitumor effects of 1-hexylcarbamoyl-5-fluorouracil combined with hyperthermia on Ehrlich ascites tumor in vivo and Nakahara-Fukuoka sarcoma cell in vitro","volume":"48","author":"Tsumura","year":"1988","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hahn, G.M. (1982). Responses of murine tumors and normal tissues. Hyperthermia and Cancer, Springer.","DOI":"10.1007\/978-1-4684-4193-2_5"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/11\/1770\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:33:27Z","timestamp":1760189607000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/11\/1770"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,11]]},"references-count":24,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["cancers11111770"],"URL":"https:\/\/doi.org\/10.3390\/cancers11111770","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2019,11,11]]}}}