Unique metabolic features of pancreatic cancer stroma: Relevance to the tumor compartment, prognosis, and invasive potential

Oncotarget

Volumn 7, Issue 48, 2016, Pages 78396-78411

  Knudsen, Erik S ^a,b,c   Balaji, Uthra ^a   Freinkman, Elizaveta ^d   McCue, Peter ^e   Witkiewicz, Agnieszka K ^a,b,c  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF ARIZONA   (United States)

^c UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

^d WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

^e THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Hypoxia; Lactate; Metastasis; Pancreatic cancer; Tumor metabolism

Indexed keywords

GLUTAMINE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; MONOCARBOXYLATE TRANSPORTER 4; CA9 PROTEIN, HUMAN; CARBONATE DEHYDRATASE IX; GLUCOSE; HIF1A PROTEIN, HUMAN; MONOCARBOXYLATE TRANSPORTER; MUSCLE PROTEIN; SLC16A4 PROTEIN, HUMAN; TUMOR ANTIGEN;

ADENOCARCINOMA CELL LINE; ARTICLE; CANCER ASSOCIATED FIBROBLAST; CANCER SURVIVAL; CANCER TISSUE; CELL INVASION; CITRIC ACID CYCLE; CONTROLLED STUDY; GENETIC TRANSFECTION; GLYCOLYSIS; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOBLOTTING; IMMUNOHISTOCHEMISTRY; MAJOR CLINICAL STUDY; METABOLISM; METABOLOMICS; PANCREAS ADENOCARCINOMA; PHENOTYPE; PLASMID; PROGNOSIS; PROTEIN DEPLETION; PROTEIN EXPRESSION; PROTEIN METABOLISM; PROTEIN STABILITY; PROTEIN SYNTHESIS; RNA INTERFERENCE; STROMA; TISSUE MICROARRAY; TUMOR MICROENVIRONMENT; TUMOR XENOGRAFT; ANIMAL; CELL MOTION; CELL PROLIFERATION; ENERGY METABOLISM; EPITHELIAL MESENCHYMAL TRANSITION; GENE EXPRESSION REGULATION; GENETIC TRANSCRIPTION; GENETICS; KAPLAN MEIER METHOD; MORTALITY; MOUSE; PANCREAS CARCINOMA; PANCREAS TUMOR; PATHOLOGY; PROPORTIONAL HAZARDS MODEL; SECONDARY; STROMA CELL; TIME FACTOR; TUMOR CELL LINE; TUMOR HYPOXIA; TUMOR INVASION;

ANIMALS; ANTIGENS, NEOPLASM; CANCER-ASSOCIATED FIBROBLASTS; CARBONIC ANHYDRASE IX; CARCINOMA, PANCREATIC DUCTAL; CELL LINE, TUMOR; CELL MOVEMENT; CELL PROLIFERATION; ENERGY METABOLISM; EPITHELIAL-MESENCHYMAL TRANSITION; GENE EXPRESSION REGULATION, NEOPLASTIC; GLUCOSE; GLUTAMINE; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; KAPLAN-MEIER ESTIMATE; MICE; MONOCARBOXYLIC ACID TRANSPORTERS; MUSCLE PROTEINS; NEOPLASM INVASIVENESS; PANCREATIC NEOPLASMS; PHENOTYPE; PROPORTIONAL HAZARDS MODELS; RNA INTERFERENCE; STROMAL CELLS; TIME FACTORS; TRANSCRIPTION, GENETIC; TRANSFECTION; TUMOR HYPOXIA; TUMOR MICROENVIRONMENT;

EID: 84998812275     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.11893     Document Type: Article

References (48)

1. Le A, Rajeshkumar NV, Maitra A, Dang CV. Conceptual framework for cutting the pancreatic cancer fuel supply. Clin Cancer Res. 2012; 18: 4285-90. doi: 10.1158/1078-0432.CCR-12-0041.
2. Knudsen ES, O'Reilly EM, Brody JR, Witkiewicz AK. Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine. Gastroenterology. 2015 doi: 10.1053/j.gastro.2015.08.056.
3. Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol. 2008; 3: 157-88. doi: 10.1146/annurev. pathmechdis.3.121806.154305.
4. Paulson AS, Tran Cao HS, Tempero MA, Lowy AM. Therapeutic advances in pancreatic cancer. Gastroenterology. 2013; 144: 1316-26. doi: 10.1053/j. gastro.2013.01.078.
5. Saif MW. Advancements in the management of pancreatic cancer: 2013. JOP. 2013; 14: 112-8. doi: 10.6092/1590-8577/1481.
6. Almhanna K, Philip PA. Defining new paradigms for the treatment of pancreatic cancer. Curr Treat Options Oncol. 2011; 12: 111-25. doi: 10.1007/s11864-011-0150-8.
7. Dang CV. Links between metabolism and cancer. Genes Dev. 2012; 26: 877-90. doi: 10.1101/gad.189365.112.
8. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008; 7: 11-20. doi: 10.1016/j.cmet.2007.10.002.
9. Sousa CM, Kimmelman AC. The Complex landscape of pancreatic cancer metabolism. Carcinogenesis. 2014. doi: 10.1093/carcin/bgu097.
10. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012; 149: 656-70. doi: 10.1016/j.cell.2012.01.058.
11. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006; 126: 107-20. doi: 10.1016/j.cell.2006.05.036.
12. Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci. 2014; 39: 91-100. doi: 10.1016/j.tibs.2013.12.004.
13. Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, DePinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2016; 30: 355-85. doi: 10.1101/gad.275776.115.
14. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013; 496: 101-5. doi: 10.1038/nature12040.
15. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, Grabocka E, Nofal M, Drebin JA, Thompson CB, Rabinowitz JD, Metallo CM, Vander Heiden MG, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013; 497: 633-7. doi: 10.1038/nature12138.
16. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A. 2007; 104: 19345-50. doi: 10.1073/pnas.0709747104.
17. Daemen A, Peterson D, Sahu N, McCord R, Du X, Liu B, Kowanetz K, Hong R, Moffat J, Gao M, Boudreau A, Mroue R, Corson L, et al. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc Natl Acad Sci U S A. 2015; 112: E4410-7. doi: 10.1073/pnas.1501605112.
18. Baek G, Tse YF, Hu Z, Cox D, Buboltz N, McCue P, Yeo CJ, White MA, DeBerardinis RJ, Knudsen ES, Witkiewicz AK. MCT4 Defines a Glycolytic Subtype of Pancreatic Cancer with Poor Prognosis and Unique Metabolic Dependencies. Cell Rep. 2014; 9: 2233-49. doi: 10.1016/j. celrep.2014.11.025.
19. Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, Rashid NU, Williams LA, Eaton SC, Chung AH, Smyla JK, Anderson JM, Kim HJ, et al. Virtual microdissection identifies distinct tumor-and stromaspecific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015. doi: 10.1038/ng.3398.
20. Olivares O, Vasseur S. Metabolic rewiring of pancreatic ductal adenocarcinoma: New routes to follow within the maze. Int J Cancer. 2016; 138: 787-96. doi: 10.1002/ijc.29501.
21. Ide T, Kitajima Y, Miyoshi A, Ohtsuka T, Mitsuno M, Ohtaka K, Miyazaki K. The hypoxic environment in tumorstromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor/c-Met signaling. Ann Surg Oncol. 2007; 14: 2600-7. doi: 10.1245/s10434-007-9435-3.
22. Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, Lolkema MP, Buchholz M, Olive KP, Gress TM, Tuveson DA. Stromal biology and therapy in pancreatic cancer. Gut. 2010; 60: 861-8. doi: gut.2010.226092 [pii] 10.1136/gut.2010.226092.
23. Palm W, Park Y, Wright K, Pavlova NN, Tuveson DA, Thompson CB. The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1. Cell. 2015; 162: 259-70 doi: 10.1016/j.cell.2015.06.017.
24. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009; 324: 1457-61. doi: 1171362 [pii] 10.1126/science.1171362.
25. Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, Ji B, Evans DB, Logsdon CD. Cancerassociated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008; 68: 918-26. doi: 68/3/918 [pii] 10.1158/0008-5472.CAN-07-5714.
26. Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, Connor F, Van Dyke T, Kozlov S, Martin P, Tseng TW, Dawson DW, et al. Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014; 159: 80-93. doi: 10.1016/j.cell.2014.08.007.
27. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, Westphalen CB, Kitajewski J, Fernandez-Barrena MG, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014; 25: 735-47. doi: 10.1016/j.ccr.2014.04.021.
28. Lee JJ, Perera RM, Wang H, Wu DC, Liu XS, Han S, Fitamant J, Jones PD, Ghanta KS, Kawano S, Nagle JM, Deshpande V, Boucher Y, et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci U S A. 2014; 111: E3091-100. doi: 10.1073/pnas.1411679111.
29. Hartwell KA, Miller PG, Mukherjee S, Kahn AR, Stewart AL, Logan DJ, Negri JM, Duvet M, Jaras M, Puram R, Dancik V, Al-Shahrour F, Kindler T, et al. Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. Nat Chem Biol. 2013; 9: 840-8. doi: 10.1038/nchembio.1367.
30. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J. 1999; 343 Pt 2: 281-99 doi:
31. Dhup S, Dadhich RK, Porporato PE, Sonveaux P. Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des. 18: 1319-30. doi: CPD-EPUB-20120223-008 [pii].
32. Halestrap AP, Wilson MC. The monocarboxylate transporter family role and regulation. IUBMB Life. 64: 109-19. doi: 10.1002/iub.572.
33. Enerson BE, Drewes LR. Molecular features, regulation, and function of monocarboxylate transporters: implications for drug delivery. J Pharm Sci. 2003; 92: 1531-44. doi: 10.1002/jps.10389.
34. Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest. 2013; 123: 3685-92. doi: 10.1172/JCI69741.
35. Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem. 2006; 281: 9030-7. doi: 10.1074/jbc. M511397200.
36. Chiche J, Ricci JE, Pouyssegur J. Tumor hypoxia and metabolism towards novel anticancer approaches. Ann Endocrinol (Paris). 2013; 74: 111-4. doi: 10.1016/j. ando.2013.02.004.
37. Vonlaufen A, Phillips PA, Xu Z, Goldstein D, Pirola RC, Wilson JS, Apte MV. Pancreatic stellate cells and pancreatic cancer cells: an unholy alliance. Cancer Res. 2008; 68: 7707-10. doi: 10.1158/0008-5472.CAN-08-1132.
38. Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z, Parker NR, Toi CS, Pirola RC, Wilson JS, Goldstein D, Apte MV. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 2008; 68: 2085-93. doi: 10.1158/0008-5472.CAN-07-2477.
39. McDonald PC, Dedhar S. Carbonic anhydrase IX (CAIX) as a mediator of hypoxia-induced stress response in cancer cells. Subcell Biochem. 2014; 75: 255-69. doi: 10.1007/978-94-007-7359-2_13.
40. Parks SK, Chiche J, Pouyssegur J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat Rev Cancer. 2013; 13: 611-23. doi: 10.1038/nrc3579.
41. Kaelin WG, Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002; 2: 673-82. doi: 10.1038/nrc885.
42. Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 2008; 8: 705-13. doi: 10.1038/nrc2468.
43. Webb BA, Chimenti M, Jacobson MP, Barber DL. Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer. 2011; 11: 671-7. doi: 10.1038/nrc3110.
44. Hui EP, Chan AT, Pezzella F, Turley H, To KF, Poon TC, Zee B, Mo F, Teo PM, Huang DP, Gatter KC, Johnson PJ, Harris AL. Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res. 2002; 8: 2595-604 doi:
45. Tan HL, Sood A, Rahimi HA, Wang W, Gupta N, Hicks J, Mosier S, Gocke CD, Epstein JI, Netto GJ, Liu W, Isaacs WB, De Marzo AM, et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res. 2014; 20: 890-903. doi: 10.1158/1078-0432.ccr-13-1982.
46. Witkiewicz AK, Whitaker-Menezes D, Dasgupta A, Philp NJ, Lin Z, Gandara R, Sneddon S, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Using the "reverse Warburg effect" to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle. 2012; 11: 1108-17. doi: 10.4161/cc.11.6.19530.
47. Wang K, Ma W, Wang J, Yu L, Zhang X, Wang Z, Tan B, Wang N, Bai B, Yang S, Liu H, Zhu S, Cheng Y. Tumorstroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma. J Thorac Oncol. 2012; 7: 1457-61. doi: 10.1097/JTO.0b013e318260dfe8.
48. Franco J, Balaji U, Freinkman E, Witkiewicz AK, Knudsen ES. Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities. Cell Rep. 2016. doi: 10.1016/j. celrep.2015.12.094.