Mechanismen der Metastasierung und Zellmobilität – die Rolle des Stoffwechsels

Zusammenfassung

Die Tumormetastasierung ist verantwortlich für über 90% der tumorassoziierten Mortalität. Etwa ein Drittel der Brustkrebspatientinnen im Frühstadium entwickeln Metastasen. Die als „metastatische Kaskade“ oder „metastatischer Zyklus“ bezeichnete Transformation in der Tumorentwicklung ist ein komplexes und mehrstufiges Geschehen. Während allgemein anerkannt ist, dass die epithelial-mesenchymale Transformation (EMT) eine entscheidende Rolle bei der Krebsprogression und -metastasierung spielt, werden die metabolischen Vorgänge in diesem Prozess bisher wenig beachtet. Daher wollen wir hier einen kurzen Überblick über den Einfluss des Metabolismus auf die Progression und Metastasierung der Tumoren geben.

Schlüsselwörter

Brustkrebs - Metastasierung - Stoffwechsel - aerobe Glykolyse

• References/Literatur

• 1 Berg JM, Stryer L, Tymoczko JL. et al. Biochemistry. New York: WH Freeman; 2015
• 2 Nordstrom L, Achanna S, Naka K. et al. Fetal and maternal lactate increase during active second stage of labour. BJOG 2001; 108: 263-268
• 3 Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012; 21: 297-308
• 4 Warburg O. Über den Stoffwechsel der Carcinomzelle. Naturwissenschaften 1924; 12: 1131-1137
• 5 Warburg O, Wind F, Negelein E. THE METABOLISM OF TUMORS IN THE BODY. J Gen Physiol 1927; 8: 519-530
• 6 Marin-Hernandez A, Gallardo-Perez JC, Hernandez-Resendiz I. et al. Hypoglycemia Enhances Epithelial-Mesenchymal Transition and Invasiveness, and Restrains the Warburg Phenotype, in Hypoxic HeLa Cell Cultures and Microspheroids. J Cell Physiol 2017; 232: 1346-1359
• 7 Warburg O. On the origin of cancer cells. Science 1956; 123: 309-314
• 8 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674
• 9 Koivunen P, Lee S, Duncan CG. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 2012; 483: 484-488
• 10 Xu W, Yang H, Liu Y. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19: 17-30
• 11 Guo J, Wang B, Fu Z. et al. Hypoxic Microenvironment Induces EMT and Upgrades Stem-Like Properties of Gastric Cancer Cells. Technol Cancer Res Treat 2016; 15: 60-68
• 12 Matsuoka J, Yashiro M, Doi Y. et al. Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGFbeta signaling. PLoS One 2013; 8: e62310
• 13 Shen X, Xue Y, Si Y. et al. The unfolded protein response potentiates epithelial-to-mesenchymal transition (EMT) of gastric cancer cells under severe hypoxic conditions. Med Oncol 2015; 32: 447
• 14 Zhang H, Sun L, Xiao X. et al. Kruppel-like factor 8 contributes to hypoxia-induced MDR in gastric cancer cells. Cancer Sci 2014; 105: 1109-1115
• 15 Zhou J, Li K, Gu Y. et al. Transcriptional up-regulation of RhoE by hypoxia-inducible factor (HIF)-1 promotes epithelial to mesenchymal transition of gastric cancer cells during hypoxia. Biochem Biophys Res Commun 2011; 415: 348-354
• 16 Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11: 85-95
• 17 Pfeiffer T, Schuster S, Bonhoeffer S. Cooperation and competition in the evolution of ATP-producing pathways. Science 2001; 292: 504-507
• 18 Dai C, Sun F, Zhu C. et al. Tumor environmental factors glucose deprivation and lactic acidosis induce mitotic chromosomal instability–an implication in aneuploid human tumors. PLoS One 2013; 8: e63054
• 19 Wu H, Ding Z, Hu D. et al. Central role of lactic acidosis in cancer cell resistance to glucose deprivation-induced cell death. J Pathol 2012; 227: 189-199
• 20 Xie J, Wu H, Dai C. et al. Beyond Warburg effect–dual metabolic nature of cancer cells. Sci Rep 2014; 4: 4927
• 21 Eckert MA, Santiago-Medina M, Lwin TM. et al. ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions. J Cell Sci 2017; 130: 2036-2048
• 22 Shi L, Pan H, Liu Z. et al. Roles of PFKFB3 in cancer. Signal Transduct Target Ther 2017; 2: 17044
• 23 Draoui N, de Zeeuw P, Carmeliet P. Angiogenesis revisited from a metabolic perspective: role and therapeutic implications of endothelial cell metabolism. Open Biol 2017; 7: pii:170219
• 24 Hu X, Chao M, Wu H. Central role of lactate and proton in cancer cell resistance to glucose deprivation and its clinical translation. Signal Transduct Target Ther 2017; 2: 16047
• 25 Liang J, Shao SH, Xu ZX. et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 2007; 9: 218-224
• 26 Schild T, Low V, Blenis J. et al. Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization. Cancer Cell 2018; 33: 347-354
• 27 Lopez-Soto A, Gonzalez S, Smyth MJ. et al. Control of Metastasis by NK Cells. Cancer Cell 2017; 32: 135-154
• 28 Nieto MA, Huang RY, Jackson RA. et al. EMT: 2016. Cell 2016; 166: 21-45
• 29 Brabletz T, Kalluri R, Nieto MA. et al. EMT in cancer. Nat Rev Cancer 2018; 18: 128-134
• 30 Pastushenko I, Brisebarre A, Sifrim A. et al. Identification of the tumour transition states occurring during EMT. Nature 2018; 556: 463-468
• 31 Thompson EW, Nagaraj SH. Transition states that allow cancer to spread. Nature 2018; 556: 442-444
• 32 Polasik A, Tzschaschel M, Schochter F. et al. Circulating Tumour Cells, Circulating Tumour DNA and Circulating MicroRNA in Metastatic Breast Carcinoma – What is the Role of Liquid Biopsy in Breast Cancer?. Geburtsh Frauenheilk 2017; 77: 1291-1298
• 33 Massague J, Obenauf AC. Metastatic colonization by circulating tumour cells. Nature 2016; 529: 298-306
• 34 Obenauf AC, Massague J. Surviving at a Distance: Organ-Specific Metastasis. Trends Cancer 2015; 1: 76-91
• 35 Mathew A, Rajagopal PS, Villgran V. et al. Distinct Pattern of Metastases in Patients with Invasive Lobular Carcinoma of the Breast. Geburtsh Frauenheilk 2017; 77: 660-666
• 36 Lehuede C, Dupuy F, Rabinovitch R. et al. Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis. Cancer Res 2016; 76: 5201-5208
• 37 Zhu A, Lee D, Shim H. Metabolic positron emission tomography imaging in cancer detection and therapy response. Semin Oncol 2011; 38: 55-69
• 38 Zhu A, Shim H. Current molecular imaging positron emitting radiotracers in oncology. Nucl Med Mol Imaging 2011; 45: 1-14
• 39 Mazurek S, Boschek CB, Hugo F. et al. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol 2005; 15: 300-308
• 40 Dong G, Mao Q, Xia W. et al. PKM2 and cancer: The function of PKM2 beyond glycolysis. Oncol Lett 2016; 11: 1980-1986
• 41 He X, Du S, Lei T. et al. PKM2 in carcinogenesis and oncotherapy. Oncotarget 2017; 8: 110656-110670
• 42 Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 2011; 10: 671-684
• 43 Luengo A, Gui DY, Vander Heiden MG. Targeting Metabolism for Cancer Therapy. Cell Chem Biol 2017; 24: 1161-1180
• 44 Taran FA, Schneeweiss A, Lux MP. et al. Update Breast Cancer 2018 (Part 1) – Primary Breast Cancer and Biomarkers. Geburtsh Frauenheilk 2018; 78: 237-245
• 45 Schneeweiss A, Lux MP, Janni W. et al. Update Breast Cancer 2018 (Part 2) – Advanced Breast Cancer, Quality of Life and Prevention. Geburtsh Frauenheilk 2018; 78: 246-259