Stromal biology and therapy in pancreatic cancer: A changing paradigm

Gut

Volumn 64, Issue 9, 2015, Pages 1476-1484

  Neesse, Albrecht ^a   Algül, Hana ^b   Tuveson, David A ^c   Gress, Thomas M ^d  

^a UNIVERSITY MEDICAL CENTER GÖTTINGEN   (Germany)

^b TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^c Pancreatic Cancer Research Laboratory ^*  (United States)

^d UNIVERSITY HOSPITAL MARBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

FLUOROURACIL; FOLINIC ACID; GEMCITABINE; HYALURONIDASE; IRINOTECAN; JANUS KINASE INHIBITOR; LOSARTAN; OXALIPLATIN; PAMREVLUMAB; ANTINEOPLASTIC AGENT;

ARTICLE; BONE MARROW CELL; CARCINOGENESIS; CELL ACTIVATION; CELL INFILTRATION; CHRONIC INFLAMMATION; DRUG EFFICACY; FIBROBLAST; HISTOPATHOLOGY; HUMAN; IMMUNOCOMPETENT CELL; MACROPHAGE; MYOFIBROBLAST; NONHUMAN; PANCREAS ADENOCARCINOMA; PANCREATIC STELLATE CELL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; STROMA; T LYMPHOCYTE; TUMOR GROWTH; ANIMAL; CARCINOMA, PANCREATIC DUCTAL; DRUG EFFECTS; FORECASTING; IMMUNOHISTOCHEMISTRY; MOUSE; NEEDLE BIOPSY; PANCREATIC NEOPLASMS; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY; PROGNOSIS; STROMA CELL; TUMOR MICROENVIRONMENT;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOPSY, NEEDLE; CARCINOMA, PANCREATIC DUCTAL; FORECASTING; HUMANS; IMMUNOHISTOCHEMISTRY; MICE; PANCREATIC NEOPLASMS; PROGNOSIS; STROMAL CELLS; TUMOR MICROENVIRONMENT;

EID: 84941271406     PISSN: 00175749     EISSN: 14683288     Source Type: Journal    
DOI: 10.1136/gutjnl-2015-309304     Document Type: Article

References (111)

1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.
2. Burris HA III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403-13.
3. Moore MJ, Goldstein D, Hamm J, et al. 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. J Clin Oncol 2007;25:1960-6.
4. Wacker B, Nagrani T, Weinberg J, et al. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 2007;13:3913-21.
5. Berlin JD, Catalano P, Thomas JP, et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 2002;20:3270-5.
6. Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 2007;25:2212-17.
7. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005;23:3509-16.
8. Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009;27:3778-85.
9. Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 2006;24:3946-52.
10. Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale. Cancer 2002;94:902-10.
11. Rocha Lima CM, Green MR, Rotche R, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004;22:3776-83.
12. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.
13. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703.
14. Feig C, Gopinathan A, Neesse A, et al. The pancreas cancer microenvironment. Clin Cancer Res 2012;18:4266-76.
15. Stoker MG, Shearer M, O'Neill C. Growth inhibition of polyoma-transformed cells by contact with static normal fibroblasts. J Cell Sci 1966;1:297-310.
16. Neesse A, Michl P, Frese KK, et al. Stromal biology and therapy in pancreatic cancer. Gut 2011;60:861-8.
17. Korc M. Pancreatic cancer-associated stroma production. Am J Surg 2007;194:S84-6.
18. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74.
19. Erkan M, Hausmann S, Michalski CW, et al. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 2012;9:454-67.
20. Perez-Mancera PA, Guerra C, Barbacid M, et al. What we have learned about pancreatic cancer from mouse models. Gastroenterology 2012;142:1079-92.
21. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324:1457-61.
22. Bramhall SR, Rosemurgy A, Brown PD, et al, Marimastat Pancreatic Cancer Study Group. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001;19:3447-55.
23. Bramhall SR, Schulz J, Nemunaitis J, et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002;87:161-7.
24. Moore MJ, Hamm J, Dancey J, et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:3296-302.
25. Gore J, Korc M. Pancreatic cancer stroma: friend or foe? Cancer Cell 2014;25:711-12.
26. Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Cancer Res 2000;6:2969-72.
27. Almoguera C, Shibata D, Forrester K, et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988;53:549-54.
28. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350-3.
29. Hezel AF, Kimmelman AC, Stanger BZ, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006;20:1218-49.
30. Pellegata NS, Sessa F, Renault B, et al. K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res 1994;54:1556-60.
31. Ohlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med 2014;211:1503-23.
32. Frese KK, Tuveson DA. Maximizing mouse cancer models. Nat Rev Cancer 2007;7:645-58.
33. Mazur PK, Siveke JT. Genetically engineered mouse models of pancreatic cancer: unravelling tumour biology and progressing translational oncology. Gut 2012;61:1488-500.
34. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4:437-50.
35. Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7:469-83.
36. Ijichi H, Chytil A, Gorska AE, et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Genes Dev 2006;20:3147-60.
37. Aguirre AJ, Bardeesy N, Sinha M, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003;17:3112-26.
38. Bardeesy N, Aguirre AJ, Chu GC, 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.
39. Neesse A, Hahnenkamp A, Griesmann H, et al. Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions. Gut 2013;62:1034-43.
40. Cook N, Frese KK, Bapiro TE, et al. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J Exp Med 2012;209:437-44.
41. Neesse A, Frese KK, Chan DS, et al. SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut 2014;63:974-83.
42. Schonhuber N, Seidler B, Schuck K, et al. A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat Med 2014;20:1340-7.
43. Ying H, Kimmelman AC, Lyssiotis CA, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012;149:656-70.
44. Collins MA, Bednar F, Zhang Y, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 2012;122:639-53.
45. Saborowski M, Saborowski A, Morris JP IV, et al. A modular and flexible ESC-based mouse model of pancreatic cancer. Genes Dev 2014;28:85-97.
46. Rad R, Rad L, Wang W, et al. PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice. Science 2010;330:1104-7.
47. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491:399-405.
48. Perez-Mancera PA, Rust AG, van der Weyden L, et al. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature 2012;486:266-70.
49. Olive KP, Politi K. Translational therapeutics in genetically engineered mouse models of cancer. Cold Spring Harb Protoc 2014;2014:131-43.
50. Sastra SA, Olive KP. Quantification of murine pancreatic tumors by high-resolution ultrasound. Methods Mol Biol 2013;980:249-66.
51. Longati P, Jia X, Eimer J, et al. 3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing. BMC Cancer 2013;13:95.
52. Kadaba R, Birke H, Wang J, et al. Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes. J Pathol 2013;230:107-17.
53. Coleman SJ, Chioni AM, Ghallab M, et al. Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion. EMBO Mol Med 2014;6:467-81.
54. Coleman SJ, Watt J, Arumugam P, et al. Pancreatic cancer organotypics: High throughput, preclinical models for pharmacological agent evaluation. World J Gastroenterol 2014;20:8471-81.
55. Boj SF, Hwang CI, Baker LA, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 2015;160:324-38.
56. Bang UC, Benfield T, Hyldstrup L, et al. Mortality, cancer, and comorbidities associated with chronic pancreatitis: a Danish nationwide matched-cohort study. Gastroenterology 2014;146:989-94.
57. Guerra C, Schuhmacher AJ, Canamero M, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007;11:291-302.
58. Wormann SM, Diakopoulos KN, Lesina M, et al. The immune network in pancreatic cancer development and progression. Oncogene 2014;33:2956-67.
59. Baumgart S, Chen NM, Siveke JT, et al. Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. Cancer Discov 2014;4:688-701.
60. Baumgart S, Glesel E, Singh G, et al. Restricted heterochromatin formation links NFATc2 repressor activity with growth promotion in pancreatic cancer. Gastroenterology 2012;142:388-98.e1-7.
61. Bachem MG, Schunemann M, Ramadani M, et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005;128:907-21.
62. Ene-Obong A, Clear AJ, Watt J, et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 2013;145:1121-32.
63. Froeling FE, Feig C, Chelala C, et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology. 2011;141:1486-97, 97.e1-14.
64. Vonlaufen A, Joshi S, Qu C, et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res 2008;68:2085-93.
65. Protti MP, De Monte L. Immune infiltrates as predictive markers of survival in pancreatic cancer patients. Front Physiol 2013;4:210.
66. Biswas SK, Allavena P, Mantovani A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol 2013;35:585-600.
67. Galdiero MR, Garlanda C, Jaillon S, et al. Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol 2013;228:1404-12.
68. Kuhnemuth B, Muhlberg L, Schipper M, et al. CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-kappaB signaling. Oncogene 2015;34:177-87.
69. Germano G, Frapolli R, Belgiovine C, et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 2013;23:249-62.
70. Weizman N, Krelin Y, Shabtay-Orbach A, et al. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene 2014;33:3812-19.
71. Frese KK, Neesse A, Cook N, et al. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2012;2:260-9.
72. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011;19:456-69.
73. Fukuda A, Wang SC, Morris JP IV, et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 2011;19:441-55.
74. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012;21:309-22.
75. Clark CE, Hingorani SR, Mick R, et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007;67:9518-27.
76. Pylayeva-Gupta Y, Lee KE, Hajdu CH, et al. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012;21:836-47.
77. Bayne LJ, Beatty GL, Jhala N, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012;21:822-35.
78. Stromnes IM, Brockenbrough JS, Izeradjene K, et al. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 2014;63:1769-81.
79. Zhang J, Han S, Zhang B, et al. Cancer immunology and cancer immunodiagnosis. J Immunol Res 2014;2014:725691.
80. McAllister F, Bailey JM, Alsina J, et al. Oncogenic Kras activates a hematopoieticto- epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 2014;25:621-37.
81. De Monte L, Reni M, Tassi E, et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med 2011;208:469-78.
82. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011;331:1612-16.
83. Ochi A, Graffeo CS, Zambirinis CP, et al. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J Clin Invest 2012;122:4118-29.
84. Ochi A, Nguyen AH, Bedrosian AS, et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med 2012;209:1671-87.
85. Stylianopoulos T, Jain RK. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc Natl Acad Sci U S A 2013;110:18632-7.
86. Stromnes IM, DelGiorno KE, Greenberg PD, et al. Stromal reengineering to treat pancreas cancer. Carcinogenesis 2014;35:1451-60.
87. Tammi RH, Kultti A, Kosma VM, et al. Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan. Semin Cancer Biol 2008;18:288-95.
88. Kultti A, Zhao C, Singha NC, et al. Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment. Biomed Res Int 2014;2014:817613.
89. Thompson CB, Shepard HM, O'Connor PM, et al. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol Cancer Ther 2010;9:3052-64.
90. Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:418-29.
91. Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 2013;62:112-20.
92. Chauhan VP, Martin JD, Liu H, et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 2013;4:2516.
93. Neesse A, Frese KK, Bapiro TE, 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.
94. Koay EJ, Baio FE, Ondari A, et al. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer. Phys Biol 2014;11:065002.
95. Koay EJ, Truty MJ, Cristini V, et al. Transport properties of pancreatic cancer describe gemcitabine delivery and response. J Clin Invest 2014;124:1525-36.
96. Marechal R, Bachet JB, Mackey JR, et al. Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology 2012;143:664-74.e1-6.
97. Greenhalf W, Ghaneh P, Neoptolemos JP, et al. Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. J Natl Cancer Inst 2014;106:djt347.
98. Rhim AD, Oberstein PE, Thomas DH, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 2014;25:735-47.
99. Marechal R, Jean-Baptiste B, Annabelle C, et al. Sonic Hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. Clin Cancer Res 2015;21:1215-24.
100. Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012;487:500-4.
101. Sherman MH, Yu RT, Engle DD, et al. Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014;159:80-93.
102. Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res 2014;2:187-93.
103. Watt J, Kocher HM. The desmoplastic stroma of pancreatic cancer is a barrier to immune cell infiltration. Oncoimmunology 2013;2:e26788.
104. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860-7.
105. Erez N, Truitt M, Olson P, et al. Cancer-associated fibroblasts are activated in incipient Neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 2010;17:135-47.
106. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6:392-401.
107. Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 2013;110:20212-17.
108. Roberts EW, Deonarine A, Jones JO, et al. Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia. J Exp Med 2013;210:1137-51.
109. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014;25:719-34.
110. Erkan M, Michalski CW, Rieder S, et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol 2008;6:1155-61.
111. Wang WQ, Liu L, Xu HX, et al. Intratumoral alpha-SMA enhances the prognostic potency of CD34 associated with maintenance of microvessel integrity in hepatocellular carcinoma and pancreatic cancer. PLoS One 2013;8:e71189.