Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy

Cancer Discovery

Volumn 6, Issue 8, 2016, Pages 852-869

  Incio, Joao ^a,b,c   Liu, Hao ^a,d   Suboj, Priya ^a,e   Chin, Shan M ^a   Chen, Ivy X ^a,f   Pinter, Matthias ^a   Ng, Mei R ^a   Nia, Hadi T ^a   Grahovac, Jelena ^a   Kao, Shannon ^a   Babykutty, Suboj ^a,g   Huang, Yuhui ^a,h   Jung, Keehoon ^a   Rahbari, Nuh N ^a,i   Han, Xiaoxing ^a   Chauhan, Vikash P ^a,j   Martin, John D ^a,k   Kahn, Julia ^a   Huang, Peigen ^a   Desphande, Vikram ^a   Michaelson, James ^a   Michelakos, Theodoros P ^d   Ferrone, Cristina R ^a,d   Soares, Raquel ^c   Boucher, Yves ^a   Fukumura, Dai ^a   Jain, Rakesh K ^a   more..

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b HOSPITAL DE SÃO JOÃO   (Portugal)

^c UNIVERSITY OF PORTO   (Portugal)

^d HARVARD MEDICAL SCHOOL   (United States)

^e St Xavier's College   (India)

^f HARVARD UNIVERSITY   (United States)

^g MAR IVANIOS COLLEGE   (India)

^h SOOCHOW UNIVERSITY   (China)

ⁱ DRESDEN UNIVERSITY OF TECHNOLOGY   (Germany)

^j MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^k UNIVERSITY OF TOKYO   (Japan)

more..

Author keywords

[No Author keywords available]

Indexed keywords

COLLAGEN TYPE 1; CXCL1 CHEMOKINE; FLUOROURACIL; INTERLEUKIN 12; INTERLEUKIN 6; LOSARTAN; TUMOR NECROSIS FACTOR ALPHA; ANGIOTENSIN 1 RECEPTOR; ANGIOTENSIN 1 RECEPTOR ANTAGONIST; INTERLEUKIN 1BETA;

ADIPOCYTE; ANALYSIS OF VARIANCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER CHEMOTHERAPY; CANCER GROWTH; CONTROLLED STUDY; DIET; EPITHELIAL MESENCHYMAL TRANSITION; EXTRACELLULAR MATRIX; FIBROSIS; GENOTYPE PHENOTYPE CORRELATION; IMMUNOFLUORESCENCE TEST; INFLAMMATION; MALE; MEAN ARTERIAL PRESSURE; MOUSE; MULTIVARIATE ANALYSIS; NONHUMAN; OBESITY; PANCREAS CANCER; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; TUMOR GROWTH; TUMOR MICROENVIRONMENT; ADIPOSE TISSUE; ANIMAL; BIOLOGICAL MODEL; BODY MASS; CARCINOMA, PANCREATIC DUCTAL; COMPLICATION; DISEASE COURSE; DISEASE MODEL; DRUG EFFECTS; DRUG RESISTANCE; GENETIC PREDISPOSITION; HUMAN; IMMUNOLOGY; KNOCKOUT MOUSE; LIPID DIET; METABOLISM; MULTIMODALITY CANCER THERAPY; NEUTROPHIL; PANCREATIC NEOPLASMS; PATHOLOGY; TUMOR VOLUME;

ADIPOSE TISSUE; ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS; ANIMALS; BODY MASS INDEX; CARCINOMA, PANCREATIC DUCTAL; COMBINED MODALITY THERAPY; DIET, HIGH-FAT; DISEASE MODELS, ANIMAL; DISEASE PROGRESSION; DRUG RESISTANCE, NEOPLASM; FIBROSIS; GENETIC PREDISPOSITION TO DISEASE; HUMANS; INFLAMMATION; INTERLEUKIN-1BETA; MALE; MICE; MICE, KNOCKOUT; MODELS, BIOLOGICAL; NEUTROPHILS; OBESITY; PANCREATIC NEOPLASMS; RECEPTOR, ANGIOTENSIN, TYPE 1; SIGNAL TRANSDUCTION; TUMOR BURDEN; TUMOR MICROENVIRONMENT;

EID: 84982872436     PISSN: 21598274     EISSN: 21598290     Source Type: Journal    
DOI: 10.1158/2159-8290.CD-15-1177     Document Type: Article

References (73)

1. American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015.
2. Genkinger JM., Spiegelman D., Anderson KE., Bernstein L., van den Brandt PA., Calle EE., et al. A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk. Int J Cancer 2011. 129. 1708–17.
3. Yuan C., Bao Y., Wu C., Kraft P., Ogino S., Ng K., et al. Prediagnostic body mass index and pancreatic cancer survival. J Clin Oncol 2013. 31. 4229–34.
4. Calle EE., Rodriguez C., Walker-Thurmond K., Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003. 348. 1625–38.
5. McWilliams RR., Matsumoto ME., Burch PA., Kim GP., Halfdanarson TR., de Andrade M., et al. Obesity adversely affects survival in pancreatic cancer patients. Cancer 2010. 116. 5054–62.
6. Li D., Morris JS., Liu J., Hassan MM., Day RS., Bondy ML., et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 2009. 301. 2553–62.
7. Smits MM., van Geenen EJ. The clinical signifi cance of pancreatic steatosis. Nat Rev Gastroenterol Hepatol 2011. 8. 169–77.
8. Ogden CL., Carroll MD., Kit BK., Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 2014; 311: 806–14.
9. Dvorak HF. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986. 315. 1650–9.
10. Whatcott CJ., Diep CH., Jiang P., Watanabe A., LoBello J., Sima C., et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res 2015. 21. 3561–8.
11. Olive KP., Jacobetz MA., Davidson CJ., Gopinathan A., McIntyre D., Honess D., et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324: 1457–61.
12. Hwang RF., Moore T., Arumugam T., Ramachandran V., Amos KD., Rivera A., et al. Cancer-associated stromal fi broblasts promote pancreatic tumor progression. Cancer Res 2008. 68. 918–26.
13. Neesse A., Frese KK., Bapiro TE., Nakagawa T., Sternlicht MD., Seeley TW., et al. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc Natl Acad Sci U S A 2013. 110. 12325–30.
14. Stylianopoulos T., Martin JD., Chauhan VP., Jain SR., Diop-Frimpong B., Bardeesy N., et al. Causes, consequences, and remedies for growthinduced solid stress in murine and human tumors. Proc Natl Acad Sci U S A 2012. 109. 15101–8.
15. Chauhan VP., Boucher Y., Ferrone CR., Roberge S., Martin JD., Stylianopoulos T., et al. Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fl uid pressure. Cancer Cell 2014. 26. 14–5.
16. Alvarez R., Musteanu M., Garcia-Garcia E., Lopez-Casas PP., Megias D., Guerra C., et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer 2013. 109. 926–33.
17. Hidalgo M., Von Hoff DD. Translational therapeutic opportunities in ductal adenocarcinoma of the pancreas. Clin Cancer Res 2012. 18. 4249–56.
18. Chauhan VP., Martin JD., Liu H., Lacorre DA., Jain SR., Kozin S V, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels. Nat Commun 2013. 4. 2516.
19. Endrich B., Reinhold HS., Gross JF., Intaglietta M. Tissue perfusion inhomogeneity during early tumor growth in rats. J Natl Cancer Inst 1979. 62. 387–95.
20. Costa C., Incio J., Soares R. Angiogenesis and chronic infl ammation: cause or consequence? Angiogenesis 2007. 10. 149–66.
21. Hosogai N., Fukuhara A., Oshima K., Miyata Y., Tanaka S., Segawa K., et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007. 56. 901–11.
22. Gonzalez-Perez RR., Rueda BR. Tumor angiogenesis regulators. Boca Raton. Taylor & Francis. 2013.
23. AGTR1 (angiotensin II receptor, type 1) gene expression. Biogps.org (http://biogps.org/#goto=genereport&id=185). In Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, et al. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 2009;10:R130.
24. Sun K., Tordjman J., Clement K., Scherer PE. Fibrosis and adipose tissue dysfunction. Cell Metab 2013. 18. 470–7.
25. Mathur A., Marine M., Lu D., Swartz-Basile DA., Saxena R., Zyromski NJ., et al. Nonalcoholic fatty pancreas disease. HPB (Oxford) 2007. 9. 312–8.
26. Matsuda A., Makino N., Tozawa T., Shirahata N., Honda T., Ikeda Y., et al. Pancreatic fat accumulation, fi brosis, and acinar cell injury in the Zucker diabetic fatty rat fed a chronic high-fat diet. Pancreas 2014. 43. 735–43.
27. Zyromski NJ., Mathur A., Pitt HA., Wade TE., Wang S., Nakshatri P., et al. Obesity potentiates the growth and dissemination of pancreatic cancer. Surgery 2009. 146. 258–63.
28. Hori M., Takahashi M., Hiraoka N., Yamaji T., Mutoh M., Ishigamori R., et al. Association of pancreatic Fatty infi ltration with pancreatic ductal adenocarcinoma. Clin Translat Gastroenterol 2014. 5. e53.
29. Hefetz-Sela S., Scherer PE. Adipocytes: Impact on tumor growth and potential sites for therapeutic intervention. Pharmacol Therapeut 2013. 138. 197–210.
30. Incio J., Tam J., Rahbari NN., Suboj P., McManus DT., Chin SM., et al. PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity. Clin Cancer Res 2016;22:2993–3004.
31. Bracci PM. Obesity and pancreatic cancer: Overview of epidemiologic evidence and biologic mechanisms. Mol Carcinog 2012. 51. 53–63.
32. Hingorani SR., Wang L., Multani AS., Combs C., Deramaudt TB., Hruban RH., et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer cell 2005. 7. 469–83.
33. Kawaguchi Y., Cooper B., Gannon M., Ray M., MacDonald RJ., Wright CV. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nature genetics 2002. 32. 128–34.
34. Kanasaki K., Koya D. Biology of obesity: Lessons from animal models of obesity. J Biomed Biotechnol 2011. 2011. 197636.
35. Collins MA., Bednar F., Zhang Y., Brisset JC., Galban S., Galban CJ., et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 2012. 122. 639–53.
36. Neoptolemos JP., Moore MJ., Cox TF., Valle JW., Palmer DH., McDonald AC., et al. Effect of adjuvant chemotherapy with fl uorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA 2012. 308. 147–56.
37. Yang F., Chung AC., Huang XR., Lan HY. Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and -independent Smad pathways: The role of Smad3. Hypertension 2009. 54. 877–84.
38. Hama K., Ohnishi H., Yasuda H., Ueda N., Mashima H., Satoh Y., et al. Angiotensin II stimulates DNA synthesis of rat pancreatic stellate cells by activating ERK through EGF receptor transactivation. Biochem Biophys Res Commun 2004. 315. 905–11.
39. Hama K., Ohnishi H., Aoki H., Kita H., Yamamoto H., Osawa H., et al. Angiotensin II promotes the proliferation of activated pancreatic stellate cells by Smad7 induction through a protein kinase C pathway. Biochem Biophys Res Commun 2006. 340. 742–50.
40. Weisberg SP., McCann D., Desai M., Rosenbaum M., Leibel RL., Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003. 112. 1796–808.
41. Fukumura D., Incio J., Shankaraiah RC., Jain RK. Obesity and cancer: An angiogenic and infl ammatory link. Microcirculation 2016. 23. 191–206.
42. White PB., True EM., Ziegler KM., Wang SS., Swartz-Basile DA., Pitt HA., et al. Insulin, leptin, and tumoral adipocytes promote murine pancreatic cancer growth. J Gastroint Surg 2010. 14. 1888–93. discussion 93–4.
43. Philip B., Roland CL., Daniluk J., Liu Y., Chatterjee D., Gomez SB., et al. A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. Gastroenterology 2013. 145. 1449–58.
44. Khasawneh J., Schulz MD., Walch A., Rozman J., Hrabe de Angelis M., Klingenspor M., et al. Infl ammation and mitochondrial fatty acid beta-oxidation link obesity to early tumor promotion. Proc Natl Acad Sci U S A 2009. 106. 3354–9.
45. Dirat B., Bochet L., Dabek M., Daviaud D., Dauvillier S., Majed B., et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 2011. 71. 2455–65.
46. Wang YY., Lehuede C., Laurent V., Dirat B., Dauvillier S., Bochet L., et al. Adipose tissue and breast epithelial cells: A dangerous dynamic duo in breast cancer. Cancer Lett 2012. 324. 142–51.
47. Hursting SD. Minireview: The year in obesity and cancer. Mol Endocrinol 2012. 26. 1961–6.
48. Hursting SD., Dunlap SM. Obesity, metabolic dysregulation, and cancer: A growing concern and an infl ammatory (and microenvironmental) issue. Ann N Y Acad Sci 2012. 1271. 82–7.
49. Masamune A., Satoh M., Kikuta K., Sakai Y., Satoh A., Shimosegawa T. Inhibition of p38 mitogen-activated protein kinase blocks activation of rat pancreatic stellate cells. J Pharmacol Exp Ther 2003. 304. 8–14.
50. Incio J., Suboj P., Chin SM., Vardam-Kaur T., Liu H., Hato T, et al. Metformin reduces desmoplasia in pancreatic cancer by reprogramming stellate cells and tumor-associated macrophages. PloS One 2015. 10. e0141392.
51. Felix K., Gaida MM. Neutrophil-derived proteases in the microenvironment of pancreatic cancer -active players in tumor progression. Int J Biol Sci 2016. 12. 302–13.
52. Zyromski NJ., Mathur A., Pitt HA., Lu D., Gripe JT., Walker JJ., et al. A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2008. 295. G552–8.
53. Mathur A., Zyromski NJ., Pitt HA., Al-Azzawi H., Walker JJ., Saxena R., et al. Pancreatic steatosis promotes dissemination and lethality of pancreatic cancer. J Am Coll Surg 2009. 208. 989–94. discussion 94–6.
54. Reid MD., Basturk O., Thirabanjasak D., Hruban RH., Klimstra DS., Bagci P., et al. Tumor-infi ltrating neutrophils in pancreatic neoplasia. Mod Pathol 2011. 24. 1612–9.
55. Coussens LM., Zitvogel L., Palucka AK. Neutralizing tumor-promoting chronic infl ammation: A magic bullet? Science 2013. 339. 286–91.
56. Fridlender ZG., Sun J., Kim S., Kapoor V., Cheng G., Ling L., et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 2009. 16. 183–94.
57. Chrysanthopoulou A., Mitroulis I., Apostolidou E., Arelaki S., Mikroulis D., Konstantinidis T., et al. Neutrophil extracellular traps promote differentiation and function of fi broblasts. J Pathol 2014. 233. 294–307.
58. Zhu Q., Zhang X., Zhang L., Li W., Wu H., Yuan X., et al. The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression. Cell Death Dis 2014. 5. e1295.
59. Raiden S., Pereyra Y., Nahmod V., Alvarez C., Castello L., Giordano M., et al. Losartan, a selective inhibitor of subtype AT1 receptors for angiotensin II, inhibits neutrophil recruitment in the lung triggered by fMLP. J Leukoc Biol 2000; 68: 700–6.
60. Raiden S., Giordano M., Andonegui G., Trevani AS., Lopez DH., Nahmod V., et al. Losartan, a selective inhibitor of subtype AT1 receptors for angiotensin II, inhibits the binding of N-formylmethionylleucyl- phenylalanine to neutrophil receptors. J Pharmacol Exp Ther 1997. 281. 624–8.
61. Preis M., Korc M. Signaling pathways in pancreatic cancer. Crit Rev Eukaryotic Gene Expr 2011. 21. 115–29.
62. Freeman JW., DeArmond D., Lake M., Huang W., Venkatasubbarao K., Zhao S. Alterations of cell signaling pathways in pancreatic cancer. Front Biosci 2004. 9. 1889–98.
63. Altomare DA., Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005. 24. 7455–64.
64. Gullino PM., Grantham FH. Studies on the exchange of fl uids between host and tumor. III. Regulation of blood fl ow in hepatomas and other rat tumors. J Natl Cancer Inst 1962;28. 211–29.
65. Guo X., Ma N., Wang J., Song J., Bu X., Cheng Y., et al. Increased p38- MAPK is responsible for chemotherapy resistance in human gastric cancer cells. BMC Cancer 2008. 8. 375.
66. Zheng X., Carstens JL., Kim J., Scheible M., Kaye J., Sugimoto H., et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015. 527. 525–30.
67. White PB., Ziegler KM., Swartz-Basile DA., Wang SS., Lillemoe KD., Pitt HA., et al. Obesity, but not high-fat diet, promotes murine pancreatic cancer growth. J Gastrointest Surg 2012. 16. 1680–5.
68. Tam J., Duda DG., Perentes JY., Quadri RS., Fukumura D., Jain RK. Blockade of VEGFR2 and not VEGFR1 can limit diet-induced fat tissue expansion: role of local versus bone marrow-derived endothelial cells. PloS One 2009. 4. e4974.
69. Fukumura D., Ushiyama A., Duda DG., Xu L., Tam J., Krishna V., et al. Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis. Circ Res 2003. 93. e88–97.
70. Surwit RS., Feinglos MN., Rodin J., Sutherland A., Petro AE., Opara EC., et al. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism 1995. 44. 645–51.
71. Bardeesy N., Aguirre AJ., Chu GC., Cheng KH., Lopez LV., Hezel AF., et al. Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci U S A 2006. 103. 5947–52.
72. Wang Y., Zhang Y., Yang J., Ni X., Liu S., Li Z., et al. Genomic sequencing of key genes in mouse pancreatic cancer cells. Curr Mol Med 2012. 12. 331–41.
73. Diop-Frimpong B., Chauhan VP., Krane S., Boucher Y., Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and effi cacy of nanotherapeutics in tumors. Proc Natl Acad Sci U S A 2011. 108. 2909–14.