Материал и методы

oncotomsk

Сибирский онкологический журнал

Siberian journal of oncology

1814-48612312-3168

Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences

10.21294/1814-4861-2022-21-6-131-144

oncotomsk-2385

Research Article

ОБЗОРЫ

REVIEWS

Микробиом, имунная система и рак: три стороны одной медали

Microbiome, immune system and cancer: three sides of the one medal

Белявская

В. А.

Belyavskaya

V. A.

Белявская Валентина Александровна, доктор биологических наук, профессор, ведущий научный сотрудник,

630559, пос. Кольцово

Valentina A. Belyavskaya, DSc, Professor, Leading Researcher,

630559, Koltsovo, Novosibirsk

https://orcid.org/0000-0003-1526-9013

Чердынцева

Н. В.

Cherdyntseva

N. V.

Чердынцева Надежда Викторовна, доктор биологических наук, профессор, член-корреспондент РАН, заведующая лабораторией молекулярной онкологии и иммунологии, заместитель директора, 634009, г. Томск, пер. Кооперативный, 52;

ведущий научный сотрудник лаборатории трансляционной клеточной и молекулярной биомедицины, 634050, г. Томск, ул. Ленина, 363;

научный сотрудник лаборатории генетических технологий, 634050, г. Томск, Московский тракт, 2

Nadezda V. Cherdyntseva, DSc, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Molecular Oncology and Immunology, Deputy Director for Science, 5, Kooperativny St., 634009, Tomsk;

Leading Researcher of Laboratory of Translational Cellular and Molecular Biomedicine, 36, Lenina St., 634050, Tomsk;

Researcher of the Laboratory of Genetic Technologies, 2, Moskovsky tract, 634050, Tomsk

nvch@tnimc.ru

https://orcid.org/0000-0003-0898-3075

Кжышковска

Ю. Г.

Kzhyshkovska

J. G.

Кжышковска Юлия Георгиевна, доктор биологических наук, профессор, заведующая лабораторией трансляционной клеточной и молекулярной биомедицины, 634050, г. Томск, ул. Ленина, 363;

заведующая лабораторией, 634050, г. Томск, Московский тракт, 24;

заведующая отделом врожденного иммунитета и иммунологической толерантности, медицинский факультет Маннгейма, Институт иммунологии и трансфузионной медицины, 68167, г. Маннгейм

July G. Kzhyshkovska, MD, PhD, Professor, Head of Laboratory of Translational Cellular and Molecular Biomedicine, 36, Lenina St., 634050, Tomsk;

Head of Laboratory, 2, Moskovsky tract, 634050, Tomsk;

Head of Department of Innate Immunity and Immunological Tolerance, Institute for Transfusion Medicine and Immunology, Mannheim 68167

https://orcid.org/0000-0002-0714-8927

Литвяков

Н. В.

Litvyakov

N. V.

Литвяков Николай Васильевич, доктор биологических наук, профессор РАН, заведующий лабораторией онковирусологии, 634009, г. Томск, пер. Кооперативный, 5

научный сотрудник лаборатории генетических технологий центральной научно-исследовательской лаборатории, 634050, г. Томск, Московский тракт, 2

Nikolay V. Litviakov, DSc, Professor of the Russian Academy of Sciences, Head of the Laboratory of Viral Oncology, 5, Kooperativny St., 634009, Tomsk;

Researcher of the Laboratory of Genetic Technologies of the Central Research Laboratory, 2, Moskovsky tract, 634050, Tomsk

ФБУН «Государственный научный центр вирусологии и биотехнологии «Вектор»РоссияResearch center of Virology and Biotechnology, VectorRussian Federation

Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наук; ФГАОУ ВО «Национальный исследовательский Томский государственный университет»; ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава РоссииРоссияCancer Research Institute, Тomsk National Research Medical Center, Russian Academy of Sciences; National Research Tomsk State University; Siberian State Medical University of the Ministry of Health of RussiaRussian Federation

ФГАОУ ВО «Национальный исследовательский Томский государственный университет»; ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава России; Университет ГейдельбергаГерманияNational Research Tomsk State University; Siberian State Medical University of the Ministry of Health of Russia; University of HeidelbergGermany

Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наук; ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава РоссииРоссияCancer Research Institute, Тomsk National Research Medical Center, Russian Academy of Sciences; Siberian State Medical University of the Ministry of Health of RussiaRussian Federation

2022

02012023

216131144

2023

Белявская В.А., Чердынцева Н.В., Кжышковска Ю.Г., Литвяков Н.В.

Belyavskaya V.A., Cherdyntseva N.V., Kzhyshkovska J.G., Litvyakov 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/2385

Цель исследования ‒ анализ современных представлений о взаимоотношениях микробиоты (микробиома) и организма человека в аспекте изучения патогенеза злокачественных новообразований, амбивалентного характера этих взаимодействий, роли иммунной системы и иммуновоспалительного статуса, способствующего канцерогенезу или препятствующего неопластическим процессам.

Материал и методы

Материал и методы. Поиск литературы производился в системах Medline, Cochrane Library, Elibrary и Pubmed, включались публикации, характеризующие современные результаты (глубиной около 7 лет).

Результаты

Результаты. Микробиота содержит в себе все сообщества комменсальных, симбиотических и патогенных микроорганизмов: бактерии, грибки, археи и вирусы, которые колонизируют желудочно-кишечный тракт и другие органы и ткани. Микробиом является важным фактором в патогенезе злокачественных новообразований в связи с участием в таких базовых физиологических процессах хозяина, как пищеварение, развитие и поддержание динамического баланса иммунной системы и модуляция эндокринных функций. Обсуждается влияние микробиоты разной локализации (желудочно-кишечного тракта, молочной железы, интравагинального тракта) на развитие и прогрессирование злокачественных опухолей молочной железы, колоректального рака (КРР) и рака шейки матки (РШМ). Роль микробиома в патогенезе злокачественных новообразований реализуется в: участии в неопластической трансформации эпителия; регуляции опухолевой прогрессии в условиях манифестированного злокачественного процесса; модификации терапевтического эффекта стандартных лекарственных препаратов, а также разработке оригинальных противоопухолевых агентов на основе пробиотиков. Изучение механизмов действия микробиома в организме хозяина открывает перспективы разработки новых подходов терапии рака. Особое внимание уделено механизмам иммуномодулирующего эффекта микробиоты в снижении риска малигнизации, регуляции опухолевой прогрессии, участии в противоопухолевой терапии. Обоснована клиническая целесообразность определения патогенетически значимых микробных маркеров, связанных с агрессивностью злокачественного процесса, ответом на лечение и токсичностью терапии. Особо следует обратить внимание на потенциальные механизмы взаимодействия оси рак – микробиом – пробиотики, поскольку последние могут обеспечивать модификацию процессов малигнизации, оказывать противоопухолевое действие и модулировать эффективность лекарственной терапии. Рассматриваются возможности редактирования микробиоты пробиотиками, противоопухолевые свойства (эффекты) бактерий и стратегии модификации микробиома для профилактики и лечения онкозаболеваний.

Purpose of the study to analyze current ideas about the relationship between the microbiota (microbiome) and the human body in the aspect of cancer pathogenesis, ambivalent character of these interactions, and the role of the immune system and immunoinfammatory status that promotes carcinogenesis or prevents neoplastic processes.

Material and Methods

Material and Methods. Literature search was carried out using Medline, Cochrane Library, Elibrary and PubMed systems, including publications over the last 7 years.

Results

Results. The microbiota includes all communities of commensal, symbiotic, and pathogenic microorganisms: bacteria, fungi, archaea, and viruses that colonize the gastrointestinal tract and other organs and tissues. The microbiome is an important factor in cancer pathogenesis due to its involvement in the basic physiological functions of the host, such as digestion, development of the immune system, and modulation of endocrine functions. In the review, the influence of microbiota of different locations (gastrointestinal tract, breast, intravaginal tract) on the development and progression of breast, colorectal and cervical cancers was discussed. The role of the microbiome in cancer pathogenesis is realized by the participation in neoplastic transformation of the epithelium, regulation of tumor progression under conditions of manifested malignant process, and modifcation of the therapeutic effect of standard drugs, including the development of original probiotic-based anticancer agents. The study of the mechanisms of action of the microbiome in the host organism opens up prospects for the development of new approaches to cancer therapy. Particular attention was paid to the mechanisms of the immunomodulatory effect of the microbiota in terms of reducing the risk of malignancy, regulating tumor progression and participating in antitumor therapy. The clinical significance of determining pathogenetically significant microbial markers associated with the aggressive form of cancer, response to treatment and toxicity of therapy was discussed. Particular attention should be paid to the potential mechanisms of interaction between cancer – microbiome – probiotics, since the latter can provide modification of malignancy processes, exert an antitumor effect, and modulate the effectiveness of drug therapy. The feasibility of editing the microbiota by probiotics was considered, and antitumor properties (effects) of bacteria and strategies for modifying the microbiome for the prevention and treatment of cancer were discussed.

микробиотарак молочной железырак шейки маткиколоректальный ракпробиотикииммунная система

microbiotabreast cancercervical cancercolorectal cancerprobioticsimmune system

Исследование выполнено при финансовой поддержке Российской Федерации в лице Министерства науки и высшего образования Российской Федерации (соглашение от 29 сентября 2021 г. № 075-15-2021- 1073 на тему: «Генетическое и эпигенетическое редактирование клеток опухоли и микроокружения с целью блокировки метастазирования»).

The study was supported by the Ministry of Science and Higher Education of the Russian Federation (agreement dated September 29, 2021 No. 075-15-2021-1073 “Genetic and epigenetic editing of tumor cells and microenvironment to block metastasis”.

References1

Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022; 12(1): 31–46. doi: 10.1158/2159-8290.CD-21-1059.

Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394–424. doi: 10.3322/caac.21492.

Goedert J.J., Jones G., Hua X., Xu X., Yu G., Flores R., Falk R.T., Gail M.H., Shi J., Ravel J., Feigelson H.S. Investigation of the association between the fecal microbiota and breast cancer in postmenopausal women: a population-based case-control pilot study. J Natl Cancer Inst. 2015; 107(8). doi: 10.1093/jnci/djv147.

Bobin-Dubigeon C., Luu H.T., Leuillet S., Lavergne S.N., Carton T., Le Vacon F., Michel C., Nazih H., Bard J.M. Faecal Microbiota Composition Varies between Patients with Breast Cancer and Healthy Women: A Comparative Case-Control Study. Nutrients. 2021; 13(8): 2705. doi: 10.3390/nu13082705.

Aykut B., Pushalkar S., Chen R., Li Q., Abengozar R., Kim J.I., Shadaloey S.A., Wu D., Preiss P., Verma N., Guo Y., Saxena A., Vardhan M., Diskin B., Wang W., Leinwand J., Kurz E., Kochen Rossi J.A., Hundeyin M., Zambrinis C., Li X., Saxena D., Miller G. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature. 2019; 574(7777): 264–7. doi: 10.1038/s41586-019-1608-2.

Di Modica M., Arlotta V., Sfondrini L., Tagliabue E., Triulzi T. The Link Between the Microbiota and HER2+ Breast Cancer: The New Challenge of Precision Medicine. Front Oncol. 2022; 12. doi: 10.3389/fonc.2022.947188.

Kommineni S., Bretl D.J., Lam V., Chakraborty R., Hayward M., Simpson P., Cao Y., Bousounis P., Kristich C.J., Salzman N.H. Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract. Nature. 2015; 526(7575): 719–22. doi: 10.1038/nature15524.

Lynch S.V., Pedersen O. The Human Intestinal Microbiome in Health and Disease. N Engl J Med. 2016; 375(24): 2369–79. doi: 10.1056/NEJMra1600266.

Perales-Puchalt A., Perez-Sanz J., Payne K.K., Svoronos N., Allegrezza M.J., Chaurio R.A., Anadon C., Calmette J., Biswas S., Mine J.A., Costich T.L., Nickels L., Wickramasinghe J., Rutkowski M.R., ConejoGarcia J.R. Frontline Science: Microbiota reconstitution restores intestinal integrity after cisplatin therapy. J Leukoc Biol. 2018; 103(5): 799–805. doi: 10.1002/JLB.5HI1117-446RR.

Iida N., Dzutsev A., Stewart C.A., Smith L., Bouladoux N., Weingarten R.A., Molina D.A., Salcedo R., Back T., Cramer S., Dai R.M., Kiu H., Cardone M., Naik S., Patri A.K., Wang E., Marincola F.M., Frank K.M., Belkaid Y., Trinchieri G., Goldszmid R.S. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013; 342(6161): 967–70. doi: 10.1126/science.1240527.

Routy B., Le Chatelier E., Derosa L., Duong C.P.M., Alou M.T., Daillère R., Fluckiger A., Messaoudene M., Rauber C., Roberti M.P., Fidelle M., Flament C., Poirier-Colame V., Opolon P., Klein C., Iribarren K., Mondragón L., Jacquelot N., Qu B., Ferrere G., Clémenson C., Mezquita L., Masip J.R., Naltet C., Brosseau S., Kaderbhai C., Richard C., Rizvi H., Levenez F., Galleron N., Quinquis B., Pons N., Ryffel B., MinardColin V., Gonin P., Soria J.C., Deutsch E., Loriot Y., Ghiringhelli F., Zalcman G., Goldwasser F., Escudier B., Hellmann M.D., Eggermont A., Raoult D., Albiges L., Kroemer G., Zitvogel L. Gut microbiome infuences efcacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91–7. doi: 10.1126/science.aan3706.

Zitvogel L., Ma Y., Raoult D., Kroemer G., Gajewski T.F. The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies. Science. 2018; 359(6382): 1366–70. doi: 10.1126/science.aar6918.

Gopalakrishnan V., Spencer C.N., Nezi L., Reuben A., Andrews M.C., Karpinets T.V., Prieto P.A., Vicente D., Hoffman K., Wei S.C., Cogdill A.P., Zhao L., Hudgens C.W., Hutchinson D.S., Manzo T., Petaccia de Macedo M., Cotechini T., Kumar T., Chen W.S., Reddy S.M., Szczepaniak Sloane R., Galloway-Pena J., Jiang H., Chen P.L., Shpall E.J., Rezvani K., Alousi A.M., Chemaly R.F., Shelburne S., Vence L.M., Okhuysen P.C., Jensen V.B., Swennes A.G., McAllister F., Marcelo Riquelme Sanchez E., Zhang Y., Le Chatelier E., Zitvogel L., Pons N., Austin-Breneman J.L., Haydu L.E., Burton E.M., Gardner J.M., Sirmans E., Hu J., Lazar A.J., Tsujikawa T., Diab A., Tawbi H., Glitza I.C., Hwu W.J., Patel S.P., Woodman S.E., Amaria R.N., Davies M.A., Gershenwald J.E., Hwu P., Lee J.E., Zhang J., Coussens L.M., Cooper Z.A., Futreal P.A., Daniel C.R., Ajami N.J., Petrosino J.F., Tetzlaff M.T., Sharma P., Allison J.P., Jenq R.R., Wargo J.A. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97–103. doi: 10.1126/science.aan4236.

Yang P., Wang Z., Peng Q., Lian W., Chen D. Comparison of the Gut Microbiota in Patients with Benign and Malignant Breast Tumors: A Pilot Study. Evol Bioinform Online. 2021; 17. doi: 10.1177/11769343211057573.

Terrisse S., Derosa L., Iebba V., Ghiringhelli F., Vaz-Luis I., Kroemer G., Fidelle M., Christodoulidis S., Segata N., Thomas A.M., Martin A.L., Sirven A., Everhard S., Aprahamian F., Nirmalathasan N., Aarnoutse R., Smidt M., Ziemons J., Caldas C., Loibl S., Denkert C., Durand S., Iglesias C., Pietrantonio F., Routy B., André F., Pasolli E., Delaloge S., Zitvogel L. Intestinal microbiota infuences clinical outcome and side efects of early breast cancer treatment. Cell Death & Diferentiation. 2021; 28(9): 2778–96.

Kim H.E., Kim J., Maeng S., Oh B., Hwang K.T., Kim B.S. Microbiota of Breast Tissue and Its Potential Association with Regional Recurrence of Breast Cancer in Korean Women. J Microbiol Biotechnol. 2021; 31(12): 1643–55. doi: 10.4014/jmb.2106.06039.

Zhu J., Liao M., Yao Z., Liang W., Li Q., Liu J., Yang H., Ji Y., Wei W., Tan A., Liang S., Chen Y., Lin H., Zhu X., Huang S., Tian J., Tang R., Wang Q., Mo Z. Breast cancer in postmenopausal women is associated with an altered gut metagenome. Microbiome. 2018; 6(1): 1–13. doi: 10.1186/s40168-018-0515-3.

Luu T.H., Michel C., Bard J.M., Dravet F., Nazih H., Bobin-Dubigeon C. Intestinal Proportion of Blautia sp. is Associated with Clinical Stage and Histoprognostic Grade in Patients with Early-Stage Breast Cancer. Nutr Cancer. 2017; 69(2): 267–75. doi: 10.1080/01635581.2017.1263750.

Rutkowski M.R., Stephen T.L., Svoronos N., Allegrezza M.J., Tesone A.J., Perales-Puchalt A., Brencicova E., Escovar-Fadul X., Nguyen J.M., Cadungog M.G., Zhang R., Salatino M., Tchou J., Rabinovich G.A., Conejo-Garcia J.R. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell. 2015; 27(1): 27–40. doi: 10.1016/j.ccell.2014.11.009.

Buchta Rosean C., Bostic R.R., Ferey J.C.M., Feng T.Y., Azar F.N., Tung K.S., Dozmorov M.G., Smirnova E., Bos P.D., Rutkowski M.R. Preexisting Commensal Dysbiosis Is a Host-Intrinsic Regulator of Tissue Infammation and Tumor Cell Dissemination in Hormone Receptor-Positive Breast Cancer. Cancer Res. 2019; 79(14): 3662–75. doi: 10.1158/0008-5472.CAN-18-3464.

He Z., Gharaibeh R.Z., Newsome R.C., Pope J.L., Dougherty M.W., Tomkovich S., Pons B., Mirey G., Vignard J., Hendrixson D.R., Jobin C. Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut. 2019; 68(2): 289–300. doi: 10.1136/gutjnl-2018-317200.

Wilson M.R., Jiang Y., Villalta P.W., Stornetta A., Boudreau P.D., Carrá A., Brennan C.A., Chun E., Ngo L., Samson L.D., Engelward B.P., Garrett W.S., Balbo S., Balskus E.P. The human gut bacterial genotoxin colibactin alkylates DNA. Science. 2019; 363(6428). doi: 10.1126/science.aar7785.

Pleguezuelos-Manzano C., Puschhof J., Rosendahl Huber A., van Hoeck A., Wood H.M., Nomburg J., Gurjao C., Manders F., Dalmasso G., Stege P.B., Paganelli F.L., Geurts M.H., Beumer J., Mizutani T., Miao Y., van der Linden R., van der Elst S.; Genomics England Research Consortium, Garcia K.C., Top J., Willems R.J.L., Giannakis M., Bonnet R., Quirke P., Meyerson M., Cuppen E., van Boxtel R., Clevers H. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature. 2020; 580(7802): 269–73. doi: 10.1038/s41586-020-2080-8.

Parida S., Wu S., Siddharth S., Wang G., Muniraj N., Nagalingam A., Hum C., Mistriotis P., Hao H., Talbot C.C., Konstantopoulos K., Gabrielson K.L., Sears C.L., Sharma D. A Procarcinogenic Colon Microbe Promotes Breast Tumorigenesis and Metastatic Progression and Concomitantly Activates Notch and β-Catenin AxesETBF Promotes Breast Carcinogenesis. Cancer Dis. 2021; 11(5): 1138–57. https://doi.org/10.1158/2159-8290.CD-20-0537.

Kwa M., Plottel C.S., Blaser M.J., Adams S. The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer. J Natl Cancer Inst. 2016; 108(8). doi: 10.1093/jnci/djw029.

Shapira I., Sultan K., Lee A., Taioli E. Evolving concepts: how diet and the intestinal microbiome act as modulators of breast malignancy. ISRN Oncol. 2013. doi: 10.1155/2013/693920.

Hanafi N.I., Mohamed A.S., Sheikh Abdul Kadir S.H., Othman M.H.D. Overview of Bile Acids Signaling and Perspective on the Signal of Ursodeoxycholic Acid, the Most Hydrophilic Bile Acid, in the Heart. Biomolecules. 2018; 8(4): 159. doi: 10.3390/biom8040159.

Parada Venegas D., De la Fuente M.K., Landskron G., González M.J., Quera R., Dijkstra G., Harmsen H.J.M., Faber K.N., Hermoso M.A. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Infammatory Bowel Diseases. Front Immunol. 2019; 10: 277. doi: 10.3389/fmmu.2019.00277. Erratum in: Front Immunol. 2019; 10: 1486.

Hou H., Chen D., Zhang K., Zhang W., Liu T., Wang S., Dai X., Wang B., Zhong W., Cao H. Gut microbiota-derived short-chain fatty acids and colorectal cancer: Ready for clinical translation? Cancer Lett. 2022; 526: 225–35. doi: 10.1016/j.canlet.2021.11.027.

Ma W., Zhang Y., Yu M., Wang B., Xu S., Zhang J., Li X., Ye X. Invitro and in-vivo anti-breast cancer activity of synergistic effect of berberine and exercise through promoting the apoptosis and immunomodulatory effects. Int Immunopharmacol. 2020; 87. doi: 10.1016/j.intimp.2020.106787. Erratum in: Int Immunopharmacol. 2020; 88.

Thirunavukkarasan M., Wang C., Rao A., Hind T., Teo Y.R., Siddiquee A.A., Goghari M.A.I., Kumar A.P., Herr D.R. Short-chain fatty acid receptors inhibit invasive phenotypes in breast cancer cells. PLoS One. 2017; 12(10). doi: 10.1371/journal.pone.0186334.

Semaan J., El-Hakim S., Ibrahim J.N., Safi R., Elnar A.A., El Boustany C. Comparative effect of sodium butyrate and sodium propionate on proliferation, cell cycle and apoptosis in human breast cancer cells MCF-7. Breast Cancer. 2020; 27(4): 696–705. doi: 10.1007/ s12282-020-01063-6.

Kovács T., Mikó E., Vida A., Sebő É., Toth J., Csonka T., Boratkó A., Ujlaki G., Lente G., Kovács P., Tóth D., Árkosy P., Kiss B., Méhes G., Goedert J.J., Bai P. Cadaverine, a metabolite of the microbiome, reduces breast cancer aggressiveness through trace amino acid receptors. Sci Rep. 2019; 9(1): 1–14.

Ridlon J.M., Kang D.J., Hylemon P.B., Bajaj J.S. Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014; 30(3): 332–8. doi: 10.1097/MOG.0000000000000057.

Krishnamurthy K., Wang G., Rokhfeld D., Bieberich E. Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide. Breast Cancer Res. 2008;10(6): 1–16. doi: 10.1186/bcr2211.

Gándola Y.B., Fontana C., Bojorge M.A., Luschnat T.T., Moretton M.A., Chiapetta D.A., Verstraeten S.V., González L. Concentration-dependent efects of sodium cholate and deoxycholate bile salts on breast cancer cells proliferation and survival. Mol Biol Rep. 2020; 47(5): 3521–39. doi: 10.1007/s11033-020-05442-2.

Mikó E., Vida A., Kovács T., Ujlaki G., Trencsényi G., Márton J., Sári Z., Kovács P., Boratkó A., Hujber Z., Csonka T., Antal-Szalmás P., Watanabe M., Gombos I., Csoka B., Kiss B., Vígh L., Szabó J., Méhes G., Sebestyén A., Goedert J.J., Bai P. Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness. Biochim Biophys Acta Bioenerg. 2018; 1859(9): 958–74. doi: 10.1016/j.bbabio.2018.04.002.

Perino A., Pols T.W., Nomura M., Stein S., Pellicciari R., Schoonjans K. TGR5 reduces macrophage migration through mTORinduced C/EBPβ diferential translation. J Clin Invest. 2014; 124(12): 5424–36. doi: 10.1172/JCI76289.

Pols T.W.H., Puchner T., Korkmaz H.I., Vos M., Soeters M.R., de Vries C.J.M. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor. PLoS One. 2017; 12(5). doi: 10.1371/journal.pone.0176715.

García-Castillo V., Sanhueza E., McNerney E., Onate S.A., García A. Microbiota dysbiosis: a new piece in the understanding of the carcinogenesis puzzle. J Med Microbiol. 2016; 65(12): 1347–62. doi: 10.1099/jmm.0.000371.

McKee A.M., Kirkup B.M., Madgwick M., Fowler W.J., Price C.A., Dreger S.A., Ansorge R., Makin K.A., Caim S., Le Gall G., Paveley J., Leclaire C., Dalby M., Alcon-Giner C., Andrusaite A., Feng T.Y., Di Modica M., Triulzi T., Tagliabue E., Milling S.W.F., Weilbaecher K.N., Rutkowski M.R., Korcsmáros T., Hall L.J., Robinson S.D. Antibioticinduced disturbances of the gut microbiota result in accelerated breast tumor growth. iScience. 2021; 24(9). doi: 10.1016/j.isci.2021.103012.

Lam K.C., Araya R.E., Huang A., Chen Q., Di Modica M., Rodrigues R.R., Lopès A., Johnson S.B., Schwarz B., Bohrnsen E., Cogdill A.P., Bosio C.M., Wargo J.A., Lee M.P., Goldszmid R.S. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell. 2021; 184(21): 5338–56. doi: 10.1016/j.cell.2021.09.019.

Toumazi D., El Daccache S., Constantinou C. An unexpected link: The role of mammary and gut microbiota on breast cancer development and management (Review). Oncol Rep. 2021; 45(5): 1–15. doi: 10.3892/or.2021.8031.

Nejman D., Livyatan I., Fuks G., Gavert N., Zwang Y., Geller L.T., Rotter-Maskowitz A., Weiser R., Mallel G., Gigi E., Meltser A., Douglas G.M., Kamer I., Gopalakrishnan V., Dadosh T., Levin-Zaidman S., Avnet S., Atlan T., Cooper Z.A., Arora R., Cogdill A.P., Khan M.A.W., Ologun G., Bussi Y., Weinberger A., Lotan-Pompan M., Golani O., Perry G., Rokah M., Bahar-Shany K., Rozeman E.A., Blank C.U., Ronai A., Shaoul R., Amit A., Dorfman T., Kremer R., Cohen Z.R., Harnof S., Siegal T., YehudaShnaidman E., Gal-Yam E.N., Shapira H., Baldini N., Langille M.G.I., Ben-Nun A., Kaufman B., Nissan A., Golan T., Dadiani M., Levanon K., Bar J., Yust-Katz S., Barshack I., Peeper D.S., Raz D.J., Segal E., Wargo J.A., Sandbank J., Shental N., Straussman R. The human tumor microbiome is composed of tumor type-specifc intracellular bacteria. Science. 2020; 368(6494): 973–80. doi: 10.1126/science.aay9189.

Hadzega D., Minarik G., Karaba M., Kalavska K., Benca J., Ciernikova S., Sedlackova T., Nemcova P., Bohac M., Pindak D., Klucar L., Mego M. Uncovering Microbial Composition in Human Breast Cancer Primary Tumour Tissue Using Transcriptomic RNA-seq. Int J Mol Sci. 2021; 22(16): 9058. doi: 10.3390/ijms22169058.

Smith A., Pierre J.F., Makowski L., Tolley E., Lyn-Cook B., Lu L., Vidal G., Starlard-Davenport A. Distinct microbial communities that difer by race, stage, or breast-tumor subtype in breast tissues of non-Hispanic Black and non-Hispanic White women. Sci Rep. 2019; 9(1): 1–10. doi: 10.1038/s41598-019-48348-1.

Fu A., Yao B., Dong T., Chen Y., Yao J., Liu Y., Li H., Bai H., Liu X., Zhang Y., Wang C., Guo Y., Li N., Cai S. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell. 2022; 185(8): 1356–72. doi: 10.1016/j.cell.2022.02.027.

Esposito M.V., Fosso B., Nunziato M., Casaburi G., D'Argenio V., Calabrese A., D'Aiuto M., Botti G., Pesole G., Salvatore F. Microbiome composition indicate dysbiosis and lower richness in tumor breast tissues compared to healthy adjacent paired tissue, within the same women. BMC Cancer. 2022; 22(1): 1–11. doi: 10.1186/s12885-021-09074-y.

Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012; 490(7418): 61–70. doi: 10.1038/nature11412.

Thompson K.J., Ingle J.N., Tang X., Chia N., Jeraldo P.R., WaltherAntonio M.R., Kandimalla K.K., Johnson S., Yao J.Z., Harrington S.C., Suman V.J., Wang L., Weinshilboum R.L., Boughey J.C., Kocher J.P., Nelson H., Goetz M.P., Kalari K.R. A comprehensive analysis of breast cancer microbiota and host gene expression. PLoS One. 2017; 12(11). doi: 10.1371/journal.pone.0188873.

Parida S., Sharma D. The power of small changes: Comprehensive analyses of microbial dysbiosis in breast cancer. Biochim Biophys Acta Rev Cancer. 2019; 1871(2): 392–405. doi: 10.1016/j.bbcan.2019.04.001.

Urbaniak C., Gloor G.B., Brackstone M., Scott L., Tangney M., Reid G. The Microbiota of Breast Tissue and Its Association with Breast Cancer. Appl Environ Microbiol. 2016; 82(16): 5039–48. doi: 10.1128/AEM.01235-16.

Tzeng A., Sangwan N., Jia M., Liu C.C., Keslar K.S., DownsKelly E., Fairchild R.L., Al-Hilli Z., Grobmyer S.R., Eng C. Human breast microbiome correlates with prognostic features and immunological signatures in breast cancer. Genome Med. 2021; 13(1): 1–17. doi: 10.1186/s13073-021-00874-2.

Parhi L., Alon-Maimon T., Sol A., Nejman D., Shhadeh A., Fainsod-Levi T., Yajuk O., Isaacson B., Abed J., Maalouf N., Nissan A., Sandbank J., Yehuda-Shnaidman E., Ponath F., Vogel J., Mandelboim O., Granot Z., Straussman R., Bachrach G. Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression. Nature Comm. 2020; 11(1): 1–12.

Hibberd A.A., Lyra A., Ouwehand A.C., Rolny P., Lindegren H., Cedgård L., Wettergren Y. Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention. BMJ Open Gastroenterol. 2017; 4(1). doi: 10.1136/bmjgast-2017-000145.

Kostic A.D., Chun E., Robertson L., Glickman J.N., Gallini C.A., Michaud M., Clancy T.E., Chung D.C., Lochhead P., Hold G.L., El-Omar E.M., Brenner D., Fuchs C.S., Meyerson M., Garrett W.S. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumorimmune microenvironment. Cell Host Microbe. 2013; 14(2): 207–15. doi: 10.1016/j.chom.2013.07.007.

Wong S.H., Kwong T.N.Y., Chow T.C., Luk A.K.C., Dai R.Z.W., Nakatsu G., Lam T.Y.T., Zhang L., Wu J.C.Y., Chan F.K.L., Ng S.S.M., Wong M.C.S., Ng S.C., Wu W.K.K., Yu J., Sung J.J.Y. Quantitation of faecal Fusobacterium improves faecal immunochemical test in detecting advanced colorectal neoplasia. Gut. 2017; 66(8): 1441–8. doi: 10.1136/gutjnl-2016-312766.

Zarei O., Rezania S., Mousavi A. Mycoplasma genitalium and cancer: a brief review. Asian Pac J Cancer Prev. 2013; 14(6): 3425–8. doi: 10.7314/apjcp.2013.14.6.3425.

Gagnière J., Raisch J., Veziant J., Barnich N., Bonnet R., Buc E., Bringer M.A., Pezet D., Bonnet M. Gut microbiota imbalance and colorectal cancer. World J Gastroenterol. 2016; 22(2): 501–18. doi: 10.3748/wjg.v22.i2.501.

Guo M., Xu E., Ai D. Inferring Bacterial Infltration in Primary Colorectal Tumors From Host Whole Genome Sequencing Data. Front Genet. 2019; 10: 213. doi: 10.3389/fgene.2019.00213.

Amabebe E., Anumba D.O.C. Psychosocial Stress, Cortisol Levels, and Maintenance of Vaginal Health. Front Endocrinol (Lausanne). 2018; 9: 568. doi: 10.3389/fendo.2018.00568.

Lamont R.F., Sobel J.D., Akins R.A., Hassan S.S., Chaiworapongsa T., Kusanovic J.P., Romero R. The vaginal microbiome: new information about genital tract fora using molecular based techniques. BJOG. 2011; 118(5): 533–49. doi: 10.1111/j.1471-0528.2010.02840.x.

Vásquez A., Jakobsson T., Ahrné S., Forsum U., Molin G. Vaginal lactobacillus fora of healthy Swedish women. J Clin Microbiol. 2002; 40(8): 2746–9. doi: 10.1128/JCM.40.8.2746-2749.2002.

Hyman R.W., Fukushima M., Diamond L., Kumm J., Giudice L.C., Davis R.W. Microbes on the human vaginal epithelium. Proc Natl Acad Sci USA. 2005; 102(22): 7952–7. doi: 10.1073/pnas.0503236102.

Fettweis J.M., Brooks J.P., Serrano M.G., Sheth N.U., Girerd P.H., Edwards D.J., Strauss J.F., The Vaginal Microbiome Consortium, Jefferson K.K., Buck G.A. Diferences in vaginal microbiome in African American women versus women of European ancestry. Microbiology (Reading). 2014; 160(Pt 10): 2272–82. doi: 10.1099/mic.0.081034-0.

Walenta S., Wetterling M., Lehrke M., Schwickert G., Sundfør K., Rofstad E.K., Mueller-Klieser W. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000; 60(4): 916–21.

Ilhan Z.E., Łaniewski P., Thomas N., Roe D.J., Chase D.M., HerbstKralovetz M.M. Deciphering the complex interplay between microbiota, HPV, infammation and cancer through cervicovaginal metabolic profling. EBioMedicine. 2019; 44: 675–90. doi: 10.1016/j.ebiom.2019.04.028.

Tamrakar R., Yamada T., Furuta I., Cho K., Morikawa M., Yamada H., Sakuragi N., Minakami H. Association between Lactobacillus species and bacterial vaginosis-related bacteria, and bacterial vaginosis scores in pregnant Japanese women. BMC Infect Dis. 2007; 7(1):1–8. doi: 10.1186/1471-2334-7-128.

Muzny C.A., Blanchard E., Taylor C.M., Aaron K.J., Talluri R., Griswold M.E., Redden D.T., Luo M., Welsh D.A., Van Der Pol W.J., Lefkowitz E.J., Martin D.H., Schwebke J.R. Identifcation of Key Bacteria Involved in the Induction of Incident Bacterial Vaginosis: A Prospective Study. J Infect Dis. 2018; 218(6): 966–78. doi: 10.1093/infdis/jiy243.

Wilson J.D., Lee R.A., Balen A.H., Rutherford A.J. Bacterial vaginal fora in relation to changing oestrogen levels. Int J STD AIDS. 2007; 18(5): 308–11. doi: 10.1258/095646207780749583.

Miller L., Patton D.L., Meier A., Thwin S.S., Hooton T.M., Eschenbach D.A. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal fora and epithelium. Obstet Gynecol. 2000; 96(3): 431–9. doi: 10.1016/s0029-7844(00)00906-6.

Chase D., Goulder A., Zenhausern F., Monk B., Herbst-Kralovetz M. The vaginal and gastrointestinal microbiomes in gynecologic cancers: a review of applications in etiology, symptoms and treatment. Gynecol Oncol. 2015; 138(1): 190–200. doi: 10.1016/j.ygyno.2015.04.036.

Lee J.E., Lee S., Lee H., Song Y.M., Lee K., Han M.J., Sung J., Ko G. Association of the vaginal microbiota with human papillomavirus infection in a Korean twin cohort. PLoS One. 2013; 8(5). doi: 10.1371/journal.pone.0063514.

Muñoz N., Castellsagué X., Berrington de González A., Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine. 2006; 24: 1–10. doi: 10.1016/j.vaccine.2006.05.115.

Wiik J., Sengpiel V., Kyrgiou M., Nilsson S., Mitra A., Tanbo T., Monceyron Jonassen C., Møller Tannæs T., Sjøborg K. Cervical microbiota in women with cervical intra-epithelial neoplasia, prior to and after local excisional treatment, a Norwegian cohort study. BMC Womens Health. 2019; 19(1): 1–9. doi: 10.1186/s12905-019-0727-0.

Ибрагимова М.К., Чуруксаева О.Н., Бычков В.А., Цыганов М.М., Дерюшева И.В., Шпилева О.В., Коломиец Л.А., Литвяков Н.В. Физический статус вируса папилломы человека в прогнозе рецидивирования цервикальных интраэпителиальных неоплазий различной степени тяжести. Сибирский онкологический журнал. 2018; 17(6): 70–7. doi: 10.21294/1814-4861-2018-17-6-70-77.

Ibragimova M.K., Churuksaeva O.N., Bychkov V.A., Tsyganov M.M., Deryusheva I.V., Shpileva O.V., Kolomiets L.A., Litviakov N.V. Physical status of human papillomavirus in the prognosis of recurrence of lowgrade and-high-grade cervical intraepithelial lesions. Siberian journal of oncology. 2018; 17(6): 70–7. (in Russian). doi: 10.21294/1814-4861-2018-17-6-70-77.

Lin M., Ye M., Zhou J., Wang Z.P., Zhu X. Recent Advances on the Molecular Mechanism of Cervical Carcinogenesis Based on Systems Biology Technologies. Comput Struct Biotechnol J. 2019; 17: 241–50. doi: 10.1016/j.csbj.2019.02.001.

Brusselaers N., Shrestha S., van de Wijgert J., Verstraelen H. Vaginal dysbiosis and the risk of human papillomavirus and cervical cancer: systematic review and meta-analysis. Am J Obstet Gynecol. 2019; 221(1): 9–18. doi: 10.1016/j.ajog.2018.12.011.

Larionova I., Kazakova E., Patysheva M., Kzhyshkowska J. Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages. Cancers (Basel). 2020; 12(6): 1411. doi: 10.3390/cancers12061411.

Larionova I., Tuguzbaeva G., Ponomaryova A., Stakheyeva M., Cherdyntseva N., Pavlov V., Choinzonov E., Kzhyshkowska J. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers. Front Oncol. 2020; 10. doi: 10.3389/fonc.2020.566511.

Nikitina E., Larionova I., Choinzonov E., Kzhyshkowska J. Monocytes and Macrophages as Viral Targets and Reservoirs. Int J Mol Sci. 2018; 19(9): 2821. doi: 10.3390/ijms19092821.

Matveeva O., Nechipurenko Y., Lagutkin D., Yegorov Y.E., Kzhyshkowska J. SARS-CoV-2 infection of phagocytic immune cells and COVID19 pathology: Antibody-dependent as well as independent cell entry. Front Immunol. 2022; 13. doi: 10.3389/fmmu.2022.1050478.

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