The conflicting roles of tumor stroma in pancreatic cancer and their contribution to the failure of clinical trials: a systematic review and critical appraisal

Cancer and Metastasis Reviews

Volumn 34, Issue 1, 2015, Pages 97-114

  Bijlsma, Maarten F ^a   van Laarhoven, Hanneke W M ^a  

^a UNIVERSITY OF AMSTERDAM   (Netherlands)

Author keywords

Desmoplasia; Hedgehog; Pancreatic cancer; Smooth muscle actin; Stroma

Indexed keywords

ANTINEOPLASTIC AGENT; TUMOR MARKER;

ANIMAL; CARCINOMA, PANCREATIC DUCTAL; DRUG EFFECTS; HUMAN; METABOLISM; PANCREAS; PANCREATIC NEOPLASMS; PATHOLOGY; STROMA CELL; TREATMENT OUTCOME; TUMOR MICROENVIRONMENT;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BIOMARKERS, TUMOR; CARCINOMA, PANCREATIC DUCTAL; HUMANS; PANCREAS; PANCREATIC NEOPLASMS; STROMAL CELLS; TREATMENT OUTCOME; TUMOR MICROENVIRONMENT;

EID: 84925445547     PISSN: 01677659     EISSN: 15737233     Source Type: Journal    
DOI: 10.1007/s10555-014-9541-1     Document Type: Article

References (84)

1. Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., & Matrisian, L. M. (2014). Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Research, 74, 2913–2921. doi:10.1158/0008-5472.CAN-14-0155.
2. Hidalgo, M. (2010). Pancreatic cancer. New English Journal Medicine, 362, 1605–1617. doi:10.1056/NEJMra0901557.
3. Oettle, H., Post, S., Neuhaus, P., Gellert, K., Langrehr, J., Ridwelski, K., Schramm, H., Fahlke, J., Zuelke, C., Burkart, C., Gutberlet, K., Kettner, E., Schmalenberg, H., Weigang-Koehler, K., Bechstein, W. O., Niedergethmann, M., Schmidt-Wolf, I., Roll, L., Doerken, B., & Riess, H. (2007). Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA, 297, 267–277. doi:10.1001/jama.297.3.267.
4. Neoptolemos, J. P., Stocken, D. D., Bassi, C., Ghaneh, P., Cunningham, D., Goldstein, D., Padbury, R., Moore, M. J., Gallinger, S., Mariette, C., Wente, M. N., Izbicki, J. R., Friess, H., Lerch, M. M., Dervenis, C., Olah, A., Butturini, G., Doi, R., Lind, P. A., Smith, D., Valle, J. W., Palmer, D. H., Buckels, J. A., Thompson, J., McKay, C. J., & Rawcliffe, C. L. (2010). Buchler MW (2010) Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA, 304, 1073–1081.
5. Ueno, H., Kosuge, T., Matsuyama, Y., Yamamoto, J., Nakao, A., Egawa, S., Doi, R., Monden, M., Hatori, T., Tanaka, M., Shimada, M., & Kanemitsu, K. (2009). A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. British Journal of Cancer, 101, 908–915. doi:10.1038/sj.bjc.6605256.
6. Burris, H. A., III, Moore, M. J., Andersen, J., Green, M. R., Rothenberg, M. L., Modiano, M. R., Cripps, M. C., Portenoy, R. K., Storniolo, A. M., Tarassoff, P., Nelson, R., Dorr, F. A., Stephens, C. D., & Von Hoff, D. D. (1997). Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. Journal of Clinical Oncology, 15, 2403–2413.
7. Moore, M. J., Goldstein, D., Hamm, J., Figer, A., Hecht, J. R., Gallinger, S., Au, H. J., Murawa, P., Walde, D., Wolff, R. A., Campos, D., Lim, R., Ding, K., Clark, G., Voskoglou-Nomikos, T., Ptasynski, M., & Parulekar, W. (2007). Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 25, 1960–1966. doi:10.1200/JCO.2006.07.9525.
8. Conroy, T., Desseigne, F., Ychou, M., Bouche, O., Guimbaud, R., Becouarn, Y., Adenis, A., Raoul, J. L., Gourgou-Bourgade, S., de la Fouchardiere, C., Bennouna, J., Bachet, J. B., Khemissa-Akouz, F., Pere-Verge, D., Delbaldo, C., Assenat, E., Chauffert, B., Michel, P., Montoto-Grillot, C., & Ducreux, M. (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. New English Journal Medicine, 364, 1817–825. doi:10.1056/NEJMoa1011923. 364.
9. Van Laethem, J. L., Verslype, C., Iovanna, J. L., Michl, P., Conroy, T., Louvet, C., Hammel, P., Mitry, E., Ducreux, M., Maraculla, T., Uhl, W., Van, T. G., Bachet, J. B., Marechal, R., Hendlisz, A., Bali, M., Demetter, P., Ulrich, F., Aust, D., Luttges, J., Peeters, M., Mauer, M., Roth, A., Neoptolemos, J. P., & Lutz, M. (2012). ew strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel. Annals of Oncology, 23, 570–576. doi:10.1093/annonc/mdr351.
10. Collisson, E. A., Sadanandam, A., Olson, P., Gibb, W. J., Truitt, M., Gu, S., Cooc, J., Weinkle, J., Kim, G. E., Jakkula, L., Feiler, H. S., Ko, A. H., Olshen, A. B., Danenberg, K. L., Tempero, M. A., Spellman, P. T., Hanahan, D., Gray, J. W., Collisson, E. A., Sadanandam, A., Olson, P., Gibb, W. J., Truitt, M., Gu, S., Cooc, J., Weinkle, J., Kim, G. E., Jakkula, L., Feiler, H. S., Ko, A. H., Olshen, A. B., Danenberg, K. L., Tempero, M. A., Spellman, P. T., Hanahan, D., & Gray, J. W. (2011). Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nature Medicine, 17(17), 500–503. doi:10.1038/nm.2344.
11. Samuel, N., & Hudson, T. J. (2012). The molecular and cellular heterogeneity of pancreatic ductal adenocarcinoma. Nature Reviews. Gastroenterology & Hepatology, 9, 77–87. doi:10.1038/nrgastro.2011.215.
12. Makohon-Moore, A., Brosnan, J. A., & Iacobuzio-Donahue, C. A. (2013). Pancreatic cancer genomics: insights and opportunities for clinical translation. Genome Medicine, 5, 26. doi:10.1186/gm430.
13. Wu, J., Jiao, Y., Dal, M. M., Maitra, A., de Wilde, R. F., Wood, L. D., Eshleman, J. R., Goggins, M. G., Wolfgang, C. L., Canto, M. I., Schulick, R. D., Edil, B. H., Choti, M. A., Adsay, V., Klimstra, D. S., Offerhaus, G. J., Klein, A. P., Kopelovich, L., Carter, H., Karchin, R., Allen, P. J., Schmidt, C. M., Naito, Y., Diaz, L. A., Jr., Kinzler, K. W., Papadopoulos, N., Hruban, R. H., & Vogelstein, B. (2011). Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proceedings of the National Academy of Sciences of the United States of America, 108, 21188–21193. doi:10.1073/pnas.1118046108.
14. Hruban, R. H., & Adsay, N. V. (2009). Molecular classification of neoplasms of the pancreas. Human Pathology, 40, 612–623. doi:10.1016/j.humpath.2009.01.008.
15. Kanda, M., Matthaei, H., Wu, J., Hong, S. M., Yu, J., Borges, M., Hruban, R. H., Maitra, A., Kinzler, K., Vogelstein, B., & Goggins, M. (2012). Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology, 142, 730–733. doi:10.1053/j.gastro.2011.12.042.
16. Biankin, A. V., Waddell, N., Kassahn, K. S., Gingras, M. C., Muthuswamy, L. B., Johns, A. L., Miller, D. K., Wilson, P. J., Patch, A. M., Wu, J., Chang, D. K., Cowley, M. J., Gardiner, B. B., Song, S., Harliwong, I., Idrisoglu, S., Nourse, C., Nourbakhsh, E., Manning, S., Wani, S., Gongora, M., Pajic, M., Scarlett, C. J., Gill, A. J., Pinho, A. V., Rooman, I., Anderson, M., Holmes, O., Leonard, C., Taylor, D., Wood, S., Xu, Q., Nones, K., Fink, J. L., Christ, A., Bruxner, T., Cloonan, N., Kolle, G., Newell, F., Pinese, M., Mead, R. S., Humphris, J. L., Kaplan, W., Jones, M. D., Colvin, E. K., Nagrial, A. M., Humphrey, E. S., Chou, A., Chin, V. T., Chantrill, L. A., Mawson, A., Samra, J. S., Kench, J. G., Lovell, J. A., Daly, R. J., Merrett, N. D., Toon, C., Epari, K., Nguyen, N. Q., Barbour, A., Zeps, N., Kakkar, N., Zhao, F., Wu, Y. Q., Wang, M., Muzny, D. M., Fisher, W. E., Brunicardi, F. C., Hodges, S. E., Reid, J. G., Drummond, J., Chang, K., Han, Y., Lewis, L. R., Dinh, H., Buhay, C. J., Beck, T., Timms, L., Sam, M., Begley, K., Brown, A., Pai, D., Panchal, A., Buchner, N., De, B. R., Denroche, R. E., Yung, C. K., Serra, S., Onetto, N., Mukhopadhyay, D., Tsao, M. S., Shaw, P. A., Petersen, G. M., Gallinger, S., Hruban, R. H., Maitra, A., Iacobuzio-Donahue, C. A., Schulick, R. D., Wolfgang, C. L., Morgan, R. A., Lawlor, R. T., Capelli, P., Corbo, V., Scardoni, M., Tortora, G., Tempero, M. A., Mann, K. M., Jenkins, N. A., Perez-Mancera, P. A., Adams, D. J., Largaespada, D. A., Wessels, L. F., Rust, A. G., Stein, L. D., Tuveson, D. A., Copeland, N. G., Musgrove, E. A., Scarpa, A., Eshleman, J. R., Hudson, T. J., Sutherland, R. L., Wheeler, D. A., Pearson, J. V., McPherson, J. D., Gibbs, R. A., & Grimmond, S. M. (2012). Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature, 491, 399–405. doi:10.1038/nature11547.
17. Collins, M. A., Bednar, F., Zhang, Y., Brisset, J. C., Galban, S., Galban, C. J., Rakshit, S., Flannagan, K. S., Adsay, N. V., & di Pasca, M. M. (2012). Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. Journal of Clinical Investigation, 122, 639–653. doi:10.1172/JCI59227.
18. Yachida, S., White, C. M., Naito, Y., Zhong, Y., Brosnan, J. A., Macgregor-Das, A. M., Morgan, R. A., Saunders, T., Laheru, D. A., Herman, J. M., Hruban, R. H., Klein, A. P., Jones, S., Velculescu, V., Wolfgang, C. L., & Iacobuzio-Donahue, C. A. (2012). Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clinical Cancer Research, 18, 6339–6347. doi:10.1158/1078-0432.CCR-12-1215.
19. Donahue, T. R., Tran, L. M., Hill, R., Li, Y., Kovochich, A., Calvopina, J. H., Patel, S. G., Wu, N., Hindoyan, A., Farrell, J. J., Li, X., Dawson, D. W., & Wu, H. (2012). Integrative survival-based molecular profiling of human pancreatic cancer. Clinical Cancer Research, 18, 1352–1363. doi:10.1158/1078-0432.CCR-11-1539.
20. Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B., Kamiyama, M., Hruban, R. H., Eshleman, J. R., Nowak, M. A., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., & Iacobuzio-Donahue, C. A. (2010). Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature, 467, 1114–1117. doi:10.1038/nature09515.
21. Jones, S., Zhang, X., Parsons, D. W., Lin, J. C., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., Jimeno, A., Hong, S. M., Fu, B., Lin, M. T., Calhoun, E. S., Kamiyama, M., Walter, K., Nikolskaya, T., Nikolsky, Y., Hartigan, J., Smith, D. R., Hidalgo, M., Leach, S. D., Klein, A. P., Jaffee, E. M., Goggins, M., Maitra, A., Iacobuzio-Donahue, C., Eshleman, J. R., Kern, S. E., Hruban, R. H., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V. E., & Kinzler, K. W. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 321, 1801–1806. doi:10.1126/science.1164368.
22. Erkan, M., Reiser-Erkan, C., Michalski, C. W., Kong, B., Esposito, I., Friess, H., & Kleeff, J. (2012). The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance. Current Molecular Medicine, 12, 288–303.
23. Goel, S., Duda, D. G., Xu, L., Munn, L. L., Boucher, Y., Fukumura, D., & Jain, R. K. (2011). Normalization of the vasculature for treatment of cancer and other diseases. Physiological Reviews, 91, 1071–1121. doi:10.1152/physrev.00038.2010.
24. Erkan, M., Reiser-Erkan, C., Michalski, C. W., & Kleeff, J. (2010). Tumor microenvironment and progression of pancreatic cancer. Experimental Oncology, 32, 128–131.
25. Ozdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C. C., Simpson, T. R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S. V., De Jesus-Acosta, A., Sharma, P., Heidari, P., Mahmood, U., Chin, L., Moses, H. L., Weaver, V. M., Maitra, A., Allison, J. P., LeBleu, V. S., & Kalluri, R. (2014). Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell, 25, 719–734. doi:10.1016/j.ccr.2014.04.005.
26. Rockwell, S., Dobrucki, I. T., Kim, E. Y., Marrison, S. T., & Vu, V. T. (2009). Hypoxia and radiation therapy: past history, ongoing research, and future promise. Current Molecular Medicine, 9, 442–458.
27. Kleeff, J., Beckhove, P., Esposito, I., Herzig, S., Huber, P. E., Lohr, J. M., & Friess, H. (2007). Pancreatic cancer microenvironment. International Journal of Cancer, 121, 699–705. doi:10.1002/ijc.22871.
28. McCarroll, J. A., Naim, S., Sharbeen, G., Russia, N., Lee, J., Kavallaris, M., Goldstein, D., & Phillips, P. A. (2014). Role of pancreatic stellate cells in chemoresistance in pancreatic cancer. Frontiers in Physiology, 5, 141. doi:10.3389/fphys.2014.00141.
29. Jaster, R. (2004). Molecular regulation of pancreatic stellate cell function. Molecular Cancer, 3, 26. doi:10.1186/1476-4598-3-26.
30. Erkan, M., Reiser-Erkan, C., Michalski, C. W., Deucker, S., Sauliunaite, D., Streit, S., Esposito, I., Friess, H., & Kleeff, J. (2009). Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia, 11, 497–508.
31. Sparmann, G., Kruse, M. L., Hofmeister-Mielke, N., Koczan, D., Jaster, R., Liebe, S., Wolff, D., & Emmrich, J. (2010). Bone marrow-derived pancreatic stellate cells in rats. Cell Research, 20, 288–298. doi:10.1038/cr.2010.10.
32. Akita, S., Kubota, K., Kobayashi, A., Misawa, R., Shimizu, A., Nakata, T., Yokoyama, T., Takahashi, M., & Miyagawa, S. (2012). Role of bone marrow cells in the development of pancreatic fibrosis in a rat model of pancreatitis induced by a choline-deficient/ethionine-supplemented diet. Biochemical and Biophysical Research Communications, 420, 743–749. doi:10.1016/j.bbrc.2012.03.060.
33. Scarlett, C. J., Colvin, E. K., Pinese, M., Chang, D. K., Morey, A. L., Musgrove, E. A., Pajic, M., Apte, M., Henshall, S. M., Sutherland, R. L., Kench, J. G., & Biankin, A. V. (2011). Recruitment and activation of pancreatic stellate cells from the bone marrow in pancreatic cancer: a model of tumor-host interaction. PloS One, 6, e26088. doi:10.1371/journal.pone.0026088.
34. Medema, J. P., & Vermeulen, L. (2011). Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature, 474, 318–326. doi:10.1038/nature10212.
35. De Sousa, E., Melo, V. L., Fessler, E., & Medema, J. P. (2013). Cancer heterogeneity—a multifaceted view. EMBO Reports, 14, 686–695. doi:10.1038/embor.2013.92.
36. Kadaba, R., Birke, H., Wang, J., Hooper, S., Andl, C. D., Di, M. F., Soylu, E., Ghallab, M., Bor, D., Froeling, F. E., Bhattacharya, S., Rustgi, A. K., Sahai, E., Chelala, C., Sasieni, P., & Kocher, H. M. (2013). Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes. Journal of Pathology, 230, 107–117. doi:10.1002/path.4172.
37. Coleman, S. J., Chioni, A. M., Ghallab, M., Anderson, R. K., Lemoine, N. R., Kocher, H. M., & Grose, R. P. (2014). Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion. EMBO Molecular Medicine, 6, 467–481. doi:10.1002/emmm.201302698.
38. Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ, 339, b2700.
39. Thayer, S. P., di Magliano, M. P., Heiser, P. W., Nielsen, C. M., Roberts, D. J., Lauwers, G. Y., Qi, Y. P., Gysin, S., Fernandez-del, C. C., Yajnik, V., Antoniu, B., McMahon, M., Warshaw, A. L., & Hebrok, M. (2003). Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature, 425, 851–856. doi:10.1038/nature02009.
40. Heretsch, P., Tzagkaroulaki, L., & Giannis, A. (2010). Cyclopamine and hedgehog signaling: chemistry, biology, medical perspectives. Angewandte Chemie International Edition in English, 49, 3418–3427. doi:10.1002/anie.200906967.
41. Ericson, J., Morton, S., Kawakami, A., Roelink, H., & Jessell, T. M. (1996). Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell, 87, 661–673.
42. Bailey, J. M., Swanson, B. J., Hamada, T., Eggers, J. P., Singh, P. K., Caffery, T., Ouellette, M. M., & Hollingsworth, M. A. (2008). Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clinical Cancer Research, 14, 5995–6004. doi:10.1158/1078-0432.CCR-08-0291.
43. Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M. A., Caldwell, M. E., Allard, D., Frese, K. K., Denicola, G., Feig, C., Combs, C., Winter, S. P., Ireland-Zecchini, H., Reichelt, S., Howat, W. J., Chang, A., Dhara, M., Wang, L., Ruckert, F., Grutzmann, R., Pilarsky, C., Izeradjene, K., Hingorani, S. R., Huang, P., Davies, S. E., Plunkett, W., Egorin, M., Hruban, R. H., Whitebread, N., McGovern, K., Adams, J., Iacobuzio-Donahue, C., Griffiths, J., & Tuveson, D. A. (2009). Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science, 324, 1457–1461. doi:10.1126/science.1171362.
44. Nakamura, K., Sasajima, J., Mizukami, Y., Sugiyama, Y., Yamazaki, M., Fujii, R., Kawamoto, T., Koizumi, K., Sato, K., Fujiya, M., Sasaki, K., Tanno, S., Okumura, T., Shimizu, N., Kawabe, J., Karasaki, H., Kono, T., Ii, M., Bardeesy, N., Chung, D. C., & Kohgo, Y. (2010). Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells. PloS One, 5, e8824. doi:10.1371/journal.pone.0008824.
45. Strand, M. F., Wilson, S. R., Dembinski, J. L., Holsworth, D. D., Khvat, A., Okun, I., Petersen, D., & Krauss, S. (2011). A novel synthetic smoothened antagonist transiently inhibits pancreatic adenocarcinoma xenografts in a mouse model. PloS One, 6, e19904. doi:10.1371/journal.pone.0019904.
46. Lonardo, E., Frias-Aldeguer, J., Hermann, P. C., & Heeschen, C. (2012). Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle, 11, 1282–1290. doi:10.4161/cc.19679.
47. Kayed, H., Meyer, P., He, Y., Kraenzlin, B., Fink, C., Gretz, N., Schoenberg, S. O., & Sadick, M. (2012). Evaluation of the metabolic response to cyclopamine therapy in pancreatic cancer xenografts using a clinical PET-CT system. Translational Oncology, 5, 335–343.
48. Chang, Q., Foltz, W. D., Chaudary, N., Hill, R. P., & Hedley, D. W. (2013). Tumor-stroma interaction in orthotopic primary pancreatic cancer xenografts during hedgehog pathway inhibition. International Journal of Cancer, 133, 225–234. doi:10.1002/ijc.28006.
49. Von Hoff, D. D., Ramanathan, R. K., Borad, M. J., Laheru, D. A., Smith, L. S., Wood, T. E., Korn, R. L., Desai, N., Trieu, V., Iglesias, J. L., Zhang, H., Soon-Shiong, P., Shi, T., Rajeshkumar, N. V., Maitra, A., & Hidalgo, M. (2011). Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. Journal of Clinical Oncology, 29, 4548–4554. doi:10.1200/JCO.2011.36.5742.
50. Neesse, A., Frese, K. K., Chan, D. S., Bapiro, T. E., Howat, W. J., Richards, F. M., Ellenrieder, V., Jodrell, D. I., & Tuveson, D. A. (2014). SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut, 63, 974–983. doi:10.1136/gutjnl-2013-305559.
51. Alvarez, R., Musteanu, M., Garcia-Garcia, E., Lopez-Casas, P. P., Megias, D., Guerra, C., Munoz, M., Quijano, Y., Cubillo, A., Rodriguez-Pascual, J., Plaza, C., de Vicente, E., Prados, S., Tabernero, S., Barbacid, M., Lopez-Rios, F., & Hidalgo, M. (2013). Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. British Journal of Cancer, 109, 926–933. doi:10.1038/bjc.2013.415.
52. Neesse, A., Frese, K. K., Bapiro, T. E., Nakagawa, T., Sternlicht, M. D., Seeley, T. W., Pilarsky, C., Jodrell, D. I., Spong, S. M., & Tuveson, D. A. (2013). CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proceedings of the National Academy of Sciences of the United States of America, 110, 12325–12330. doi:10.1073/pnas.1300415110.
53. Provenzano, P. P., Cuevas, C., Chang, A. E., Goel, V. K., Von Hoff, D. D., & Hingorani, S. R. (2012). Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell, 21, 418–429. doi:10.1016/j.ccr.2012.01.007.
54. Jacobetz, M. A., Chan, D. S., Neesse, A., Bapiro, T. E., Cook, N., Frese, K. K., Feig, C., Nakagawa, T., Caldwell, M. E., Zecchini, H. I., Lolkema, M. P., Jiang, P., Kultti, A., Thompson, C. B., Maneval, D. C., Jodrell, D. I., Frost, G. I., Shepard, H. M., Skepper, J. N., & Tuveson, D. A. (2013). Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut, 62, 112–120. doi:10.1136/gutjnl-2012-302529.
55. Buckway, B., Wang, Y., Ray, A., & Ghandehari, H. (2013). Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors. International Journal of Pharmaceutics, 456, 202–211. doi:10.1016/j.ijpharm.2013.07.067.
56. Hajime, M., Shuichi, Y., Makoto, N., Masanori, Y., Ikuko, K., Atsushi, K., Mutsuo, S., & Keiichi, T. (2007). Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice. International Journal of Cancer, 120, 2704–2709. doi:10.1002/ijc.22349.
57. Spector, I., Zilberstein, Y., Lavy, A., Nagler, A., Genin, O., & Pines, M. (2012). Involvement of host stroma cells and tissue fibrosis in pancreatic tumor development in transgenic mice. PloS One, 7, e41833. doi:10.1371/journal.pone.0041833.
58. Kozono, S., Ohuchida, K., Eguchi, D., Ikenaga, N., Fujiwara, K., Cui, L., Mizumoto, K., & Tanaka, M. (2013). Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells. Cancer Research, 73, 2345–2356. doi:10.1158/0008-5472.CAN-12-3180.
59. Kano MR, Bae Y, Iwata C, Morishita Y, Yashiro M, Oka M, Fujii T, Komuro A, Kiyono K, Kaminishi M, Hirakawa K, Ouchi Y, Nishiyama N, Kataoka K, Miyazono K (2007) Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proceedings of the National Academy of Sciences of the United States of America 104, 10.1073/pnas.0611660104
60. Medicherla, S., Li, L., Ma, J. Y., Kapoun, A. M., Gaspar, N. J., Liu, Y. W., Mangadu, R., O’Young, G., Protter, A. A., Schreiner, G. F., Wong, D. H., & Higgins, L. S. (2007). Antitumor activity of TGF-beta inhibitor is dependent on the microenvironment. Anticancer Research, 27, 4149–4157.
61. Gore, A. J., Deitz, S. L., Palam, L. R., Craven, K. E., & Korc, M. (2014). Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-beta to promote proliferation. Journal of Clinical Investigation, 124, 338–352. doi:10.1172/JCI71526.
62. Arnold, S. A., Rivera, L. B., Carbon, J. G., Toombs, J. E., Chang, C. L., Bradshaw, A. D., & Brekken, R. A. (2012). Losartan slows pancreatic tumor progression and extends survival of SPARC-null mice by abrogating aberrant TGFbeta activation. PloS One, 7, e31384. doi:10.1371/journal.pone.0031384.
63. Masamune, A., Hamada, S., Kikuta, K., Takikawa, T., Miura, S., Nakano, E., & Shimosegawa, T. (2013). The angiotensin II type I receptor blocker olmesartan inhibits the growth of pancreatic cancer by targeting stellate cell activities in mice. Scandinavian Journal of Gastroenterology, 48, 602–609. doi:10.3109/00365521.2013.777776.
64. Raykov, Z., Grekova, S. P., Bour, G., Lehn, J. M., Giese, N. A., Nicolau, C., & Aprahamian, M. (2014). Myo-inositol trispyrophosphate-mediated hypoxia reversion controls pancreatic cancer in rodents and enhances gemcitabine efficacy. International Journal of Cancer, 134, 2572–2582. doi:10.1002/ijc.28597.
65. Martinez-Bosch, N., Fernandez-Barrena, M. G., Moreno, M., Ortiz-Zapater, E., Munne-Collado, J., Iglesias, M., Andre, S., Gabius, H. J., Hwang, R. F., Poirier, F., Navas, C., Guerra, C., Fernandez-Zapico, M. E., & Navarro, P. (2014). Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation. Cancer Research, 74, 3512–3524. doi:10.1158/0008-5472.CAN-13-3013.
66. Feig, C., Jones, J. O., Kraman, M., Wells, R. J., Deonarine, A., Chan, D. S., Connell, C. M., Roberts, E. W., Zhao, Q., Caballero, O. L., Teichmann, S. A., Janowitz, T., Jodrell, D. I., Tuveson, D. A., & Fearon, D. T. (2013). Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 110, 20212–20217. doi:10.1073/pnas.1320318110.
67. Ijichi, H., Chytil, A., Gorska, A. E., Aakre, M. E., Bierie, B., Tada, M., Mohri, D., Miyabayashi, K., Asaoka, Y., Maeda, S., Ikenoue, T., Tateishi, K., Wright, C. V., Koike, K., Omata, M., & Moses, H. L. (2011). Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma. Journal of Clinical Investigation, 121, 4106–4117. doi:10.1172/JCI42754.
68. Mayorek, N., Naftali-Shani, N., & Grunewald, M. (2010). Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity. PloS One, 5, e12715. doi:10.1371/journal.pone.0012715.
69. Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., Dekleva, E. N., Saunders, T., Becerra, C. P., Tattersall, I. W., Westphalen, C. B., Kitajewski, J., Fernandez-Barrena, M. G., Fernandez-Zapico, M. E., Iacobuzio-Donahue, C., Olive, K. P., & Stanger, B. Z. (2014). Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell, 25, 735–747. doi:10.1016/j.ccr.2014.04.021.
70. 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, Kato T, Chen JK, Willmann JK, Bardeesy N, Beachy PA (2014) Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci U S A 111, 10.1073/pnas.1411679111
71. Von Hoff, D. D., Ervin, T., Arena, F. P., Chiorean, E. G., Infante, J., Moore, M., Seay, T., Tjulandin, S. A., Ma, W. W., Saleh, M. N., Harris, M., Reni, M., Dowden, S., Laheru, D., Bahary, N., Ramanathan, R. K., Tabernero, J., Hidalgo, M., Goldstein, D., Van, C. E., Wei, X., Iglesias, J., & Renschler, M. F. (2013). Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New England Journal of Medicine, 369, 1691–1703. doi:10.1056/NEJMoa1304369.
72. Goldstein, D., El Maraghi, R. H., Hammel, P., Heinemann, V., Kunzmann, V., Sastre, J., Scheithauer, W., Siena, S., Tabernero, J., Teixeira, L., Tortora, G., Van Laethem, J. L., Young, R., Wei, X., Lu, B., Romano, A., & Von Hoff, D. D. (2014). Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas. Journal of Clinical Oncology Meeting Abstracts, 32, 178.
73. Frese, K. K., Neesse, A., Cook, N., Bapiro, T. E., Lolkema, M. P., Jodrell, D. I., & Tuveson, D. A. (2012). nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discovery, 2, 260–269. doi:10.1158/2159-8290.CD-11-0242.
74. Catenacci, D. V. T., Bahari, N., Edelman, M. J., Nattam, S. R., de Wilton, M. R., Kaubisch, A., Wallace, J. A., Cohen, D. J., Stiff, P. J., Sleckman, B. G., Thomas, S. P., Lenz, H. J., Henderson, L., Zagaya, C., Vannier, M., Karrison, T., Stadler, W. M., & Kindler, H. L. (2012). A phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer (PC): Interim analysis of a University of Chicago phase II consortium study. Journal of Clinical Oncology Meeting Abstracts, 30, 4022.
75. Richards, D. A., Stephenson, J., Wolpin, B. M., Becerra, C., Hamm, J. T., Messersmith, W. A., Devens, S., Cushing, J., Schmalbach, T., & Fuchs, C. S. (2012). A phase Ib trial of IPI-926, a hedgehog pathway inhibitor, plus gemcitabine in patients with metastatic pancreatic cancer. Journal of Clinical Oncology Meeting Abstracts, 30, 213.
76. Palmer, S. R., Erlichman, C., Fernandez-Zapico, M., Qi, Y., Almada, L., McCleary-Wheeler, A., Borad, M. J., Molina, J. R., Grothey, H. C., Pitot, H. C., Jatoi, A., Northfelt, D. W., McWilliams, R., Okuno, H., Haluska, P., Kim, G. P., & Colon-Otero, G. (2011). Phase I trial erlotinib, gemcitabine, and the hedgehog inhibitor, GDC-0449. Journal of Clinical Oncology Meeting Abstracts, 29, 3092.
77. De Jesus-Acosta, A., O’Dwyer, P. J., Ramanathan, R. K., Von Hoff, D. D., Maitra, A., Rasheed, Z., Zheng, L., Rajeshkumar, N. V., Le, D. T., Hoering, A., Bolejack, V., Yabuuchi, S., & Laheru, D. A. (2014). A phase II study of vismodegib, a hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA). J Clinical Oncology Meeting Abstracts, 32, 257.
78. Anonymous (2012) Infinity reports update from phase 2 study of saridegib plus gemcitabine in patients with metastatic pancreatic cancer. http://www.businesswire.com/news/home/20120127005146/en/Infinity-Reports-Update-Phase-2-Study-Saridegib#U-DoOICSy6w date accessed 31-8-2014.
79. Damhofer, H., Medema, J. P., Veenstra, V. L., Badea, L., Popescu, I., Roelink, H., & Bijlsma, M. F. (2013). Assessment of the stromal contribution to Sonic Hedgehog-dependent pancreatic adenocarcinoma. Molecular Oncology, 7, 1031–1042. doi:10.1016/j.molonc.2013.08.004.
80. Flaberg, E., Markasz, L., Petranyi, G., Stuber, G., Dicso, F., Alchihabi, N., Olah, E., Csizy, I., Jozsa, T., Andren, O., Johansson, J. E., Andersson, S. O., Klein, G., & Szekely, L. (2011). High-throughput live-cell imaging reveals differential inhibition of tumor cell proliferation by human fibroblasts. International Journal of Cancer, 128, 2793–2802. doi:10.1002/ijc.25612.
81. Truty, M. J., & Urrutia, R. (2007). Transforming growth factor-beta: what every pancreatic surgeon should know. Surgery, 141, 1–6. doi:10.1016/j.surg.2006.07.019.
82. Harsha, H. C., Kandasamy, K., Ranganathan, P., Rani, S., Ramabadran, S., Gollapudi, S., Balakrishnan, L., Dwivedi, S. B., Telikicherla, D., Selvan, L. D., Goel, R., Mathivanan, S., Marimuthu, A., Kashyap, M., Vizza, R. F., Mayer, R. J., Decaprio, J. A., Srivastava, S., Hanash, S. M., Hruban, R. H., & Pandey, A. (2009). A compendium of potential biomarkers of pancreatic cancer. PLoS Medicine, 6, e1000046. doi:10.1371/journal.pmed.1000046.
83. Francia, G., Cruz-Munoz, W., Man, S., Xu, P., & Kerbel, R. S. (2011). Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nature Reviews Cancer, 11, 135–141. doi:10.1038/nrc3001.
84. Lonardo, E., Hermann, P. C., Mueller, M. T., Huber, S., Balic, A., Miranda-Lorenzo, I., Zagorac, S., Alcala, S., Rodriguez-Arabaolaza, I., Ramirez, J. C., Torres-Ruiz, R., Garcia, E., Hidalgo, M., Cebrian, D. A., Heuchel, R., Lohr, M., Berger, F., Bartenstein, P., Aicher, A., & Heeschen, C. (2011). Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell, 9, 433–446. doi:10.1016/j.stem.2011.10.001.