oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2017-16-6-47-56oncotomsk-641Research ArticleЛАБОРАТОРНЫЕ И КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯLABORATORY AND CLINICAL STUDIESЭКСПРЕССИЯ МАКРОФАГ-АССОЦИИРОВАННЫХ ГЕНОВ В ОПУХОЛИ МОЛОЧНОЙ ЖЕЛЕЗЫ: СВЯЗЬ С ОПУХОЛЕВОЙ ПРОГРЕССИЕЙEXPRESSION of MACROPHAGe-ASSOCIATED GENES IN BREAST TUMORS: RELATION TO TUMOR PROGRESSIONhttps://orcid.org/0000-0002-0714-8927ЛитвяковН. В.LitviakovN. V.

доктор биологических наук, заведующий лабораторией онковирусологии

SPIN-код: 2546-0181

AuthorID: 183820

ResearchID: C-3263-2012

SCOPUS: 6506850698

PhD

SPIN-code: 2546-0181

AuthorID: 183820

nvlitv72@yandex.ruhttps://orcid.org/0000-0001-7419-4512ЦыгановМ. М.TsyganovM. M.

кандидат биологических наук, научный сотрудник лаборатории онковирусологии

SPIN-код: 1253-0240

AuthorID: 730156

ResearchID: A-7212-2014

SCOPUS: 55366377400

PhD

SPIN-code: 1253-0240

AuthorID: 730156

TsyganovMM@yandex.ruhttps://orcid.org/0000-0001-8815-2786ИбрагимоваМ. К.IbragimovaM. K.

младший научный сотрудник, лаборатории онковирусологии

SPIN-код: 2340-1628

AuthorID: 637822

ResearchID: C-8609-2012

SCOPUS: 57130579200

SPIN-code: 2340-1628

AuthorID: 637822

ResearchID: C-8609-2012

SCOPUS: 57130579200

imk1805@yandex.ruhttps://orcid.org/0000-0002-9568-3371ДерюшеваИ. В.DeryushevaI. V.

младший научный сотрудник лаборатории онковирусологии

SPIN-код: 5560-6131.

AuthorID: 881749.

ResearchID: Q-5607-2017

SPIN-code: 5560-6131

AuthorID: 881749

Irkin_097@mail.ruКазанцеваП. В.KazantsevaP. V.

кандидат медицинских наук, младший научный сотрудник отделения общей онкологии

SPIN-код: 7881-6259.

AuthorID: 857960

MD, PhD

SPIN-code: 7881-6259

AuthorID: 857960

polydoctor@yandex.ruМитрофановаИ. В.MitrofanovaI. V.

младший научный сотрудник лаборатории трансляционной клеточной и молекулярной биомедицины

SPIN-код: 6272-8422

AuthorID: 818171

ResearchID: 56862097400

MD

SPIN-code: 6272-8422

AuthorID: 56862097400

mitrof_@mail.ruhttps://orcid.org/0000-0001-5227-006XФроловаИ. Г.FrolovaI. G.

доктор медицинских наук, профессор, заведующая отделением лучевой диагностики

SPIN-код: 9800-9777

AuthorID: 463121

SCOPUS: 7006413170

MD, DSc, Professor

SPIN-code: 9800-9777

AuthorID: 463121

SCOPUS: 7006413170

FrolovaIG@oncology.tomsk.ruБулдаковМ. А.BuldakovM. A.

кандидат биологических наук, старший научный сотрудник лаборатории молекулярной онкологии и иммунологии

SPIN-код: 7558-4726

AuthorID: 135429

ResearchID: C- 7922-2012

PhD

SPIN-code: 7558-4726

AuthorID: 7922-2012

buldakov@oncology.tomsk.ruСлонимскаяЕ. М.SlonimskayaE. M.

доктор медицинских наук, профессор, заведующая отделением общей онкологии

SPIN-код: 7763-6417

AuthorID: 183823

MD, DSc, Professor

SPIN-code: 7763-6417

AuthorID: 183823

slonimskaya@rambler.ruЧойнзоновЕ. Л.ChoinzonovE. L.

академик РАН, доктор медицинских наук, профессор, директор Томского национального исследовательского медицинского центра Российской академии наук 

SPIN-код: 2240-8730

AuthorID: 550195

MD, DSc, Professor

SPIN-code: 2240-8730

AuthorID: 550195

info@oncology.tomsk.ruКжышковскаЮ. Г.KzhyshkovskaYu. G.

доктор биологических наук, профессор, заведующая отделом врожденного иммунитета и иммунологической толерантности Института иммунологии и трансфузионной медицины, медицинский факультет Маннгейма, Университет Гейдельберга (г. Гейдельберг, Германия); заведующая лабораторией трансляционной клеточной и молекулярной биомедицины, Национальный исследовательский Томский государственный университет

Professor, Tomsk State University (Tomsk, Russia); Institute of Transfusion Medicine and Immunology, Medical Faculty, Mannheim, University of Heidelberg (Mannheim, Germany)

Julia.Kzhyshkowska@gmail.comЧердынцеваН. В.CherdyntsevaN. V.

член-корреспондент РАН, доктор биологических наук, профессор, заведующая лабораторией молекулярной онкологии и иммунологии

SPINкод: 5344-0990

AuthorID: 81344

ResearchID: C-7943-2012

PhD, Professor

SPIN-code: 5344-0990

AuthorID: 81344

nvch@oncology.tomsk.ruНаучно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наук, г. Томск; ФГАОУ ВО «Национальный исследовательский Томский государственный университет», г. ТомскРоссияCancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, Tomsk; National Research Tomsk State University, TomskRussian FederationНаучно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наук, г. ТомскРоссияCancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Science, TomskRussian FederationФГАОУ ВО «Национальный исследовательский Томский государственный университет», г. Томск; Институт трансфузионной медицины и иммунологии, медицинский факультет, Университет Гейдельберга, г. ГейдельбергРоссияNational Research Tomsk State University, Tomsk; Institute of Transfusion Medicine and Immunology, Medical Faculty, Mannheim, University of Heidelberg, MannheimRussian Federation2017241220171664756Copyright © Литвяков Н.В., Цыганов М.М., Ибрагимова М.К., Дерюшева И.В., Казанцева П.В., Митрофанова И.В., Фролова И.Г., Булдаков М.А., Слонимская Е.М., Чойнзонов Е.Л., Кжышковска Ю.Г., Чердынцева Н.В., 20172017Литвяков Н.В., Цыганов М.М., Ибрагимова М.К., Дерюшева И.В., Казанцева П.В., Митрофанова И.В., Фролова И.Г., Булдаков М.А., Слонимская Е.М., Чойнзонов Е.Л., Кжышковска Ю.Г., Чердынцева Н.В.Litviakov N.V., Tsyganov M.M., Ibragimova M.K., Deryusheva I.V., Kazantseva P.V., Mitrofanova I.V., Frolova I.G., Buldakov M.A., Slonimskaya E.M., Choinzonov E.L., Kzhyshkovska Y.G., Cherdyntseva N.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/641Введение

Введение. Опухолeассоциированные макрофаги (ОАМ) являются основными клетками врожденного иммунитета, которые регулируют взаимоотношения инфильтрирующих иммунокомпетентных клеток с опухолевыми клетками и с другими компонентами микроокружения, пролиферацию опухолевых клеток, ангиогенез, а также могут вовлекаться в реализацию ответа на химиотерапию. Целью исследования является оценка прогностической значимости экспрессии маркеров опухолеассоциированных макрофагов YKL39 и CCL18 в опухоли молочной железы до лечения. Методы. Было обследовано 96 больных с морфологически верифицированной инвазивной карциномой молочной железы неспецифического типа IIa–IIIb стадии (T1–4N0–3M0), которые в неоадъювантном режиме получали 2–4 курса химиотерапии. У больных оценивали 5-летнюю безметастатическую выживаемость. Уровень экспрессии генов YKL39 и CCL18 оценивали при помощи количественной ПЦР с обратной транскрипцией в режиме реального времени (qPCR) по технологии TaqMan в опухоли до лечения. При уровне экспрессии гена более 1 (больше, чем в нормальной ткани) говорили о гиперэкспрессии гена. Результаты. Уровень экспрессии изучаемых генов не зависел от основных клинико-патологических показателей заболевания. Выявлен существенно более высокий уровень экспрессии исследуемых генов у пациентов с отсутствием отдаленных метастазов в течение 5-летнего наблюдения после лечения. По методу Каплана – Майера было проведено сравнение безметастатической выживаемости у пациентов с гиперэкспрессией указанных генов в опухоли (группа YKL39+CCL18+) и с разным сочетанием низкого и высокого уровня экспрессии (YKL39– CCL18– , YKL39– CCL18+, YKL39+CCL18– ). Без признаков прогрессирования были живы 100 % (10 из 10) больных, имеющих YKL39+CCL18+ макрофагальный фенотип в опухоли, при YKL39+CCL18– фенотипе уровень 5-летней безметастатической выживаемости составил 85 %. Два макрофагальных фенотипа связаны с более низкой 5-летней безметастатической выживаемостью: при YKL39– CCL18+ фенотипе – 71 %, при YKL39– CCL18– фенотипе – 69 %. Полученные данные показали ассоциацию экспрессии маркеров ОАМ в опухоли с показателями безметастатической выживаемости у больных раком молочной железы, получавших предоперационное лечение.

 

 

Background

Background. Tumor-associated macrophages (TAM) are the main innate immunity cells that regulate the relationship between the infiltrating immunocompetent cells, tumor cells and other components of the microenvironment. TAMs can promote tumor cell proliferation and angiogenesis and can also contribute to tumor response to chemotherapy. The purpose of the study was to assess the prognostic significance of YKL39 and CCL18 gene expression in breast TAMs prior to treatment. Material and methods. A total of 96 patients with histologically verified invasive breast carcinoma of no special type (T1–4N0–3M0) were included into the study. The patients received 2–4 cycles of neoadjuvant chemotherapy. The 5-year metastasis-free survival was analyzed. The YKL39 and CCL18 expression levels were assessed using TaqMan real-time RTPCR. The expression level of >1 (higher than that in the normal tissue) indicated the gene overexpression. Results. There was no association between the YKL39 and CCL18 gene expression levels and the clinical and pathologic features. However, the levels of YKL39 and CCL18 gene expressions were significantly higher in patients having no distant metastases within a 5-year follow-up. Metastasis-free survival was estimated in patients with overexpression of YKL39 and CCL18 genes (YKL39+CCL18+ ) and in patients with low and high expression levels (YKL39– CCL18– , YKL39– CCL18+, YKL39+CCL18– ) using the Kaplan-Meier method. All 100 % of patients (10 out of 10) with YKL39+CCL18+ macrophage phenotype in a tumor were alive and had no evidence of tumor progression during 5 years of follow-up. In patients with YKL39+CCL18– phenotype, the metastasis-free survival rate was 85 %. In patients with YKL39– CCL18+ and YKL39– CCL18– phenotypes, the 5-year survival rates were 71 % and 69 %, respectively. A statistically significant difference in metastasis-free survival between patients with YKL39+CCL18+ phenotype and YKL39– CCL18+ or YKL39– CCL18– phenotypes was found. Data obtained showed the association between TAM marker gene expression and metastasis free survival of breast cancer patients treated with NACT.

 

 

рак молочной железыопухолеассоциированные макрофагиэкспрессия геновопухолевая прогрессияbreast cancertumor-associated macrophagesgene expressiontumor progressionReferencesKaufmann M., von Minckwitz G., Mamounas E.P., Cameron D., Car-ey L.A., Cristofanilli M., Denkert C., Eiermann W., Gnant M., Harris J.R., Karn T., Liedtke C., Mauri D., Rouzier R., Ruckhaeberle E., Semiglazov V., Symmans W.F., Tutt A., Pusztai L. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012; 19 (5): 1508–16. doi: 10.1245/s10434-011-2108-2.Kaufmann M., von Minckwitz G., Mamounas E.P., Cameron D., Car-ey L.A., Cristofanilli M., Denkert C., Eiermann W., Gnant M., Harris J.R., Karn T., Liedtke C., Mauri D., Rouzier R., Ruckhaeberle E., Semiglazov V., Symmans W.F., Tutt A., Pusztai L. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012; 19 (5): 1508–16. doi: 10.1245/s10434-011-2108-2.Liu B., Ezeogu L., Zellmer L., Yu B., Xu N., Joshua Liao D. Protecting the normal in order to better kill the cancer. Cancer Med. 2015; 4 (9): 1394–403. doi: 10.1002/cam4.488.Liu B., Ezeogu L., Zellmer L., Yu B., Xu N., Joshua Liao D. Protecting the normal in order to better kill the cancer. Cancer Med. 2015; 4 (9): 1394–403. doi: 10.1002/cam4.488.Kim E.S. Chemotherapy Resistance in Lung Cancer. Lung Cancer and Personalized Medicine: Springer. 2016: 189–209. doi: 10.1007/978-3-319-24223-1_10.Kim E.S. Chemotherapy Resistance in Lung Cancer. Lung Cancer and Personalized Medicine: Springer. 2016: 189–209. doi: 10.1007/978-3-319-24223-1_10.Findlay J.M., Castro-Giner F., Makino S., Rayner E., Kartsonaki C., Cross W., Kovac M., Ulahannan D., Palles C., Gillies R.S., MacGregor T.P., Church D., Maynard N.D., Buffa F., Cazier J.B., Graham T.A., Wang L.M., Sharma R.A., Middleton M., Tomlinson I. Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy. Nat Commun. 2016 Apr 5; 7: 11111. doi: 10.1038/ncomms11111.Findlay J.M., Castro-Giner F., Makino S., Rayner E., Kartsonaki C., Cross W., Kovac M., Ulahannan D., Palles C., Gillies R.S., MacGregor T.P., Church D., Maynard N.D., Buffa F., Cazier J.B., Graham T.A., Wang L.M., Sharma R.A., Middleton M., Tomlinson I. Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy. Nat Commun. 2016 Apr 5; 7: 11111. doi: 10.1038/ncomms11111.Ibragimova M., Tsyganov M., Litviakov N. Natural and chemotherapy-induced clonal evolution of tumors. Biochemistry (Mosc). 2017 Apr; 82 (4): 413–425. doi: 10.1134/S0006297917040022.Ibragimova M., Tsyganov M., Litviakov N. Natural and chemotherapy-induced clonal evolution of tumors. Biochemistry (Mosc). 2017 Apr; 82 (4): 413–425. doi: 10.1134/S0006297917040022.De Palma M., Lewis C.E. Cancer: Macrophages limit chemotherapy. Nature. 2011 Apr 21; 472 (7343): 303–4. doi: 10.1038/472303a.De Palma M., Lewis C.E. Cancer: Macrophages limit chemotherapy. Nature. 2011 Apr 21; 472 (7343): 303–4. doi: 10.1038/472303a.Hughes R., Qian B.Z., Rowan C., Muthana M., Keklikoglou I., Olson O.C., Tazzyman S., Danson S., Addison C., Clemons M., Gonzalez-Angulo A.M., Joyce J.A., De Palma M., Pollard J.W., Lewis C.E. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 2015 Sep 1; 75 (17): 3479–91. doi: 10.1158/0008-5472. CAN-14-3587.Hughes R., Qian B.Z., Rowan C., Muthana M., Keklikoglou I., Olson O.C., Tazzyman S., Danson S., Addison C., Clemons M., Gonzalez-An-gulo A.M., Joyce J.A., De Palma M., Pollard J.W., Lewis C.E. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 2015 Sep 1; 75 (17): 3479–91. doi: 10.1158/0008-5472.CAN-14-3587.Yang J., Li X., Liu X., Liu Y. The role of tumor-associated macrophages in breast carcinoma invasion and metastasis. Int J Clin Exp Pathol. 2015 Jun 1; 8 (6): 6656–64.Yang J., Li X., Liu X., Liu Y. The role of tumor-associated macrophages in breast carcinoma invasion and metastasis. Int J Clin Exp Pathol. 2015 Jun 1; 8 (6): 6656–64.Noy R., Pollard J.W. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014; 41: 49–61. doi: 10.1016/j. immuni.2014.06.010.Noy R., Pollard J.W. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014; 41: 49–61. doi: 10.1016/j. immuni.2014.06.010.Riabov V., Gudima A., Wang N., Mickley A., Orekhov A., Kzhyshkowska J. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol. 2014; 5: 75. doi: 10.3389/ fphys.2014.00075.Riabov V., Gudima A., Wang N., Mickley A., Orekhov A., Kzhyshkowska J. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol. 2014; 5: 75. doi: 10.3389/ fphys.2014.00075.Mitchem J.B., Brennan D.J., Knolhoff B.L., Belt B.A., Zhu Y., Sanford D.E., Belaygorod L., Carpenter D., Collins L., Piwnica-Worms D., Hewitt S., Udupi G.M., Gallagher W.M., Wegner C., West B.L., Wang-Gillam A., Goedegebuure P., Linehan D.C., DeNardo D.G. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013; 73: 1128–1141. doi: 10.1158/0008-5472.Mitchem J.B., Brennan D.J., Knolhoff B.L., Belt B.A., Zhu Y., Sanford D.E., Belaygorod L., Carpenter D., Collins L., Piwnica-Worms D., Hewitt S., Udupi G.M., Gallagher W.M., Wegner C., West B.L., Wang-Gillam A., Goedegebuure P., Linehan D.C., DeNardo D.G. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013; 73: 1128–1141. doi: 10.1158/0008-5472.Zitvogel L., Galluzzi L., Smyth M.J., Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013; 39: 74–88. doi: 10.1016/j. immuni.2013.06.014.Zitvogel L., Galluzzi L., Smyth M.J., Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013; 39: 74–88. doi: 10.1016/j. immuni.2013.06.014.Mantovani A., Biswas S.K., Galdiero M.R., Sica A., Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013 Jan; 229 (2): 176–85. doi: 10.1002/path.4133.Mantovani A., Biswas S.K., Galdiero M.R., Sica A., Locati M.Mantovani A., Locati M. Tumor-Associated Macrophages as a Paradigm of Macrophage Plasticity, Diversity, and Polarization Lessons and Open Questions. Arterioscler Thromb Vasc Biol. 2013; 33: 1478–1483. doi: 10.1161/ATVBAHA.113.300168.Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013 Jan; 229 (2): 176–85. doi: 10.1002/path.4133.DeNardo D.G., Brennan D.J., Rexhepaj E., Ruffell B., Shiao S.L., Madden S.F., Gallagher W.M., Wadhwani N., Keil S.D., Junaid S.A., Rugo H.S., Hwang E.S., Jirström K., West B.L., Coussens L.M. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Disc. 2011; 1: 54–67. doi: 10.1158/2159-8274.CD-10-0028.Mantovani A., Locati M. Tumor-Associated Macrophages as a Paradigm of Macrophage Plasticity, Diversity, and Polarization Lessons and Open Questions. Arterioscler Thromb Vasc Biol. 2013; 33: 1478–1483. doi: 10.1161/ATVBAHA.113.300168.Dijkgraaf E.M., Heusinkveld M., Tummers B., Vogelpoel L.T., Goedemans R., Jha V., Nortier J.W., Welters M.J., Kroep J.R., van der Burg S.H. Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res. 2013; 73: 2480–92. doi: 10.1158/0008-5472.DeNardo D.G., Brennan D.J., Rexhepaj E., Ruffell B., Shiao S.L., Madden S.F., Gallagher W.M., Wadhwani N., Keil S.D., Junaid S.A., Rugo H.S., Hwang E.S., Jirström K., West B.L., Coussens L.M. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Disc. 2011; 1: 54–67. doi: 10.1158/2159-8274.CD-10-0028.Kzhyshkowska J., Gratchev A., Goerdt S. Human chitinases and chitinase-like proteins as indicators for inflammation and cancer. Biomarker Insights. 2007; 2: 128–46.Dijkgraaf E.M., Heusinkveld M., Tummers B., Vogelpoel L.T., Goedemans R., Jha V., Nortier J.W., Welters M.J., Kroep J.R., van der Burg S.H. Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res. 2013; 73: 2480–92. doi: 10.1158/0008-5472.Kzhyshkowska J., Yin S., Liu T., Riabov V., Mitrofanova I. Role of chitinase-like proteins in cancer. Biol Chem. 2016; 397: 231–47. doi: 10.1515/hsz-2015-0269.Kzhyshkowska J., Gratchev A., Goerdt S. Human chitinases and chitinase-like proteins as indicators for inflammation and cancer. Biomarker Insights. 2007; 2: 128–46.Shao R., Hamel K., Petersen L., Cao J.Q., Arenas R.B., Bigelow C., Bentley B., Yan W. YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene. 2009; 28: 4456. doi: 10.1038/onc.2009.292.Kzhyshkowska J., Yin S., Liu T., Riabov V., Mitrofanova I. Role of chitinase-like proteins in cancer. Biol Chem. 2016; 397: 231–47. doi: 10.1515/hsz-2015-0269.Gratchev A., Kzhyshkowska J., Kannookadan S., Ochsenreiter M., Popova A., Yu X., Mamidi S., Stonehouse-Usselmann E., Muller-Molinet I., Gooi L., Goerdt S. Activation of a TGF-β-specific multistep gene expression program in mature macrophages requires glucocorticoid-mediated surface expression of TGF-β receptor II. J Immunol. 2008; 180: 6553–65.Shao R., Hamel K., Petersen L., Cao J.Q., Arenas R.B., Bigelow C., Bentley B., Yan W. YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene. 2009; 28: 4456. doi: 10.1038/onc.2009.292.Lin L., Chen Y.S., Yao Y.D., Chen J.Q., Chen J.N., Huang S.Y., Zeng Y.J., Yao H.R., Zeng S.H., Fu Y.S., Song E.W. CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. Oncotar-get. 2015; 6: 34758–34773. doi: 10.18632/oncotarget.5325.Gratchev A., Kzhyshkowska J., Kannookadan S., Ochsenreiter M., Popova A., Yu X., Mamidi S., Stonehouse-Usselmann E., Muller-Molinet I., Gooi L., Goerdt S. Activation of a TGF-β-specific multistep gene expression program in mature macrophages requires glucocorticoid-mediated surface expression of TGF-β receptor II. J Immunol. 2008; 180: 6553–65.Chen J., Yao Y., Gong C., Yu F., Su S., Chen J., Liu B., Deng H., Wang F., Lin L., Yao H., Su F., Anderson K.S., Liu Q., Ewen M.E., Yao X., Song E. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011; 19: 541–555. doi: 10.1016/j.ccr.2011.02.006.Lin L., Chen Y.S., Yao Y.D., Chen J.Q., Chen J.N., Huang S.Y., Zeng Y.J., Yao H.R., Zeng S.H., Fu Y.S., Song E.W. CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer. Oncotar-get. 2015; 6: 34758–34773. doi: 10.18632/oncotarget.5325.Nagarsheth N., Wicha M.S., Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017 Sep 30; 17 (9): 559–572. doi: 10.1038/nri.2017.49.Chen J., Yao Y., Gong C., Yu F., Su S., Chen J., Liu B., Deng H., Wang F., Lin L., Yao H., Su F., Anderson K.S., Liu Q., Ewen M.E., Yao X., Song E. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011; 19: 541–555. doi: 10.1016/j.ccr.2011.02.006.Schwartz G.F., Hortobagyi G.N. Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26–28, 2003, Philadelphia, Pennsylvania. Cancer. 2004; 100 (12): 2512–32.Nagarsheth N., Wicha M.S., Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017 Sep 30; 17 (9): 559–572. doi: 10.1038/nri.2017.49.Wolff A.C., Hammond M.E., Hicks D.G., Dowsett M., McShane L.M., Allison K.H., Allred D.C., Bartlett J.M., Bilous M., Fitz-gibbons P., Hanna W., Jenkins R.B., Mangu P.B., Paik S., Perez E.A., Press M.F., Spears P.A., Vance G.H., Viale G., Hayes D.F.; American Society of Clinical Oncology; College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Medicine. 2007; 131: 18–43. doi: 10.1043/1543-2165(2007)131[18:ASOCCO]2.0.CO;2.Schwartz G.F., Hortobagyi G.N. Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26–28, 2003, Philadelphia, Pennsylvania. Cancer. 2004; 100 (12): 2512–32.Litviakov N.V., Cherdyntseva N.V., Tsyganov M.M., Denisov E.V., Garbukov E.Y., Merzliakova M.K., Volkomorov V.V., Vtorushin S.V., Zavyalova M.V., Slonimskaya E.M., Perelmuter V.M. Changing the expression vector of multidrug resistance genes is related to neoadjuvant chemotherapy response. Cancer Chemother Pharmacol. 2013; 71 (1): 153–63. doi: 10.1007/s00280-012-1992-x.Wolff A.C., Hammond M.E., Hicks D.G., Dowsett M., McShane L.M., Allison K.H., Allred D.C., Bartlett J.M., Bilous M., Fitz-gibbons P., Hanna W., Jenkins R.B., Mangu P.B., Paik S., Perez E.A., Press M.F., Spears P.A., Vance G.H., Viale G., Hayes D.F.; American Society of Clinical Oncology; College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Medicine. 2007; 131: 18–43. doi: 10.1043/1543-2165(2007)131[18:ASOCCO]2.0.CO;2.Litviakov N.V., Cherdyntseva N.V., Tsyganov M.M., Slonimskaya Е.M., Ibragimova M.K., Kazantseva P.V., Kzhyshkowska J., Choinzonov E.L. Deletions of multidrug resistance gene loci in breast cancer leads to the down-regulation of its expression and predict tumor response to neoadjuvant chemotherapy. Oncotarget. 2016 Feb 16; 7 (7): 7829–41. doi: 10.18632/oncotarget.6953.Litviakov N.V., Cherdyntseva N.V., Tsyganov M.M., Denisov E.V., Garbukov E.Y., Merzliakova M.K., Volkomorov V.V., Vtorushin S.V., Zavyalova M.V., Slonimskaya E.M., Perelmuter V.M. Changing the expression vector of multidrug resistance genes is related to neoadjuvant chemotherapy response. Cancer Chemother Pharmacol. 2013; 71 (1): 153–63. doi: 10.1007/s00280-012-1992-x.Pfaffl M.W., Lange I.G., Daxenberger A., Meyer H.H. Tissue-specific expression pattern of estrogen receptors (ER): quantification of ER alpha and ER beta mRNA with real-time RT-PCR. APMIS. 2001 May; 109 (5): 345–55.Litviakov N.V., Cherdyntseva N.V., Tsyganov M.M., Slonimskaya Е.M., Ibragimova M.K., Kazantseva P.V., Kzhyshkowska J., Choinzonov E.L. Deletions of multidrug resistance gene loci in breast cancer leads to the down-regulation of its expression and predict tumor response to neoadjuvant chemotherapy. Oncotarget. 2016 Feb 16; 7 (7): 7829–41. doi: 10.18632/oncotarget.6953.Martinez F.O., Helming L., Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009; 27: 451–83. doi: 10.1146/annurev.immunol.021908.132532.Pfaffl M.W., Lange I.G., Daxenberger A., Meyer H.H. Tissue-specific expression pattern of estrogen receptors (ER): quantification of ER alpha and ER beta mRNA with real-time RT-PCR. APMIS. 2001 May; 109 (5): 345–55.Schutyser E., Richmond A., Van Damme J. Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes. J Leukoc Biol. 2005; 78: 14–26.Martinez F.O., Helming L., Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009; 27: 451–83. doi: 10.1146/annurev.immunol.021908.132532.Kzhyshkowska J., Yin S., Liu T., Riabov V., Mitrofanova I. Role of chitinase-like proteins in cancer. Biol Chem. 2016 Mar; 397 (3): 231–47. doi: 10.1515/hsz-2015-0269.Schutyser E., Richmond A., Van Damme J. Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes. J Leukoc Biol. 2005; 78: 14–26.Leung S.Y., Yuen S.T., Chu K.M., Mathy J.A., Li R., Chan A.S., Law S., Wong J., Chen X., So S. Expression profiling identifies chemokine (C-C motif) ligand 18 as an independent prognostic indicator in gastric cancer. Gastroenterol. 2004; 127: 457–469.Kzhyshkowska J., Yin S., Liu T., Riabov V., Mitrofanova I. Role of chitinase-like proteins in cancer. Biol Chem. 2016 Mar; 397 (3): 231–47. doi: 10.1515/hsz-2015-0269.Sainz Jr. B., Martin B., Tatari M., Heeschen C., Guerra S. ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res. 2014 Dec 15; 74 (24): 7309–20. doi: 10.1158/0008-5472. CAN-14-1354.Leung S.Y., Yuen S.T., Chu K.M., Mathy J.A., Li R., Chan A.S., Law S., Wong J., Chen X., So S. Expression profiling identifies chemokine (C-C motif) ligand 18 as an independent prognostic indicator in gastric cancer. Gastroenterol. 2004; 127: 457–469.Sainz Jr. B., Martin B., Tatari M., Heeschen C., Guerra S. ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res. 2014 Dec 15; 74 (24): 7309–20. doi: 10.1158/0008-5472. CAN-14-1354.Sainz Jr. B., Martin B., Tatari M., Heeschen C., Guerra S. ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res. 2014 Dec 15; 74 (24): 7309–20. doi: 10.1158/0008-5472. CAN-14-1354.

The authors declare that there are no conflicts of interest present.