Background Galectin-1, a member of carbohydrate-binding proteins with a polyvalent function on tumor progression, was found strongly expressed in pancreatic satellite cells (PSCs), which partner in crime with cancer cells and promote the development of pancreatic ductal adenocarcinoma (PDAC). We evaluated the effects of PSCs derived Galectin-1 on the progression of PDAC, as well as the tumor establishment and development in mouse xenografts. Methods The relationship between immunohistochemistry staining intensity of Galectin-1 and clinicopathologic variables were assessed in 66 PDAC tissues, 18 chronic pancreatitis tissues and 10 normal controls. The roles of PSCs isolated from PDAC and normal pancreas on the proliferative activity, MMP2 and MMP9 expression, and the invasion of CFPAC-1 in the co-cultured system, as well as on the tumor establishment and development in mouse xenografts by mixed implanting with CFPAC-1 subcutaneously were evaluated. Results Galectin-1 expression was gradually increased from normal pancreas (negative), chronic pancreatitis (weak) to PDAC (strong), in which Galectin-1 expression was also increased from well, moderately to poorly differentiated PDAC. Galectin-1 staining intensity of pancreatic cancer tissue was associated with increase in tumor size, lymph node metastasis, perineural invasion and differentiation and UICC stage, and served as the independent prognostic indicator of poor survival of pancreatic cancer. In vitro and in vivo experiments indicated that TGF-β1 upregulated Galectin-1 expression in PSCs, which could further promotes the proliferative activity, MMP2 and MMP9 expression, and invasion of pancreatic cancer cells, as well as the tumor establishment and growth. Conclusion Galectin-1 expression in stromal cells of pancreatic cancer suggests that this protein plays a role in the promotion of cancer cells invasion and metastasis and provides a therapeutic target for the treatment of pancreatic cancer.
References
[1]
Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60: 277–300. doi: 10.3322/caac.20073
[2]
The Lancet O (2010) Pancreatic cancer: a neglected killer? Lancet Oncol 11: 1107. doi: 10.1016/s1470-2045(10)70281-3
[3]
Neesse A, Michl P, Frese KK, Feig C, Cook N, et al. (2011) Stromal biology and therapy in pancreatic cancer. Gut 60: 861–868. doi: 10.1136/gut.2010.226092
[4]
Kuroda T, Kumagi T, Yokota T, Seike H, Nishiyama M, et al. (2013) Improvement of long-term outcomes in pancreatic cancer and its associated factors within the gemcitabine era: a collaborative retrospective multicenter clinical review of 1,082 patients. BMC Gastroenterol 13: 134. doi: 10.1186/1471-230x-13-134
[5]
Luo J, Xiao L, Wu C, Zheng Y, Zhao N (2014) Correction: The Incidence and Survival Rate of Population-Based Pancreatic Cancer Patients: Shanghai Cancer Registry 2004-2009. PLoS One 9..
[6]
Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z, et al. (2008) Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res 68: 2085–2093. doi: 10.1158/0008-5472.can-07-2477
[7]
Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X, et al. (2010) Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol 177: 2585–2596. doi: 10.2353/ajpath.2010.090899
[8]
Tang D, Yuan Z, Xue X, Lu Z, Zhang Y, et al. (2012) High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int J Cancer 130: 2337–2348. doi: 10.1002/ijc.26290
[9]
Masamune A, Satoh M, Hirabayashi J, Kasai K, Satoh K, et al. (2006) Galectin-1 induces chemokine production and proliferation in pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol 290: G729–736. doi: 10.1152/ajpgi.00511.2005
[10]
Spano D, Russo R, Di Maso V, Rosso N, Terracciano LM, et al. (2010) Galectin-1 and its involvement in hepatocellular carcinoma aggressiveness. Mol Med 16: 102–115.
[11]
Wu MH, Hong TM, Cheng HW, Pan SH, Liang YR, et al. (2009) Galectin-1-mediated tumor invasion and metastasis, up-regulated matrix metalloproteinase expression, and reorganized actin cytoskeletons. Mol Cancer Res 7: 311–318. doi: 10.1158/1541-7786.mcr-08-0297
[12]
Camby I, Le Mercier M, Lefranc F, Kiss R (2006) Galectin-1: a small protein with major functions. Glycobiology 16: 137R–157R. doi: 10.1093/glycob/cwl025
[13]
Rabinovich GA (2005) Galectin-1 as a potential cancer target. Br J Cancer 92: 1188–1192.
[14]
Satelli A, Rao US (2011) Galectin-1 is silenced by promoter hypermethylation and its re-expression induces apoptosis in human colorectal cancer cells. Cancer Lett 301: 38–46. doi: 10.1016/j.canlet.2010.10.027
[15]
Bektas S, Bahadir B, Ucan BH, Ozdamar SO (2010) CD24 and galectin-1 expressions in gastric adenocarcinoma and clinicopathologic significance. Pathol Oncol Res 16: 569–577. doi: 10.1007/s12253-010-9248-8
[16]
Wang L, Friess H, Zhu Z, Frigeri L, Zimmermann A, et al. (2000) Galectin-1 and galectin-3 in chronic pancreatitis. Lab Invest 80: 1233–1241. doi: 10.1038/labinvest.3780131
[17]
Berberat PO, Friess H, Wang L, Zhu Z, Bley T, et al. (2001) Comparative analysis of galectins in primary tumors and tumor metastasis in human pancreatic cancer. J Histochem Cytochem 49: 539–549. doi: 10.1177/002215540104900414
[18]
Shen J, Person MD, Zhu J, Abbruzzese JL, Li D (2004) Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry. Cancer Res 64: 9018–9026. doi: 10.1158/0008-5472.can-04-3262
[19]
Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, et al. (2004) Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 29: 179–187. doi: 10.1097/00006676-200410000-00002
[20]
Bachem MG, Schunemann M, Ramadani M, Siech M, Beger H, et al. (2005) Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128: 907–921. doi: 10.1053/j.gastro.2004.12.036
[21]
Masamune A, Kikuta K, Watanabe T, Satoh K, Hirota M, et al. (2009) Fibrinogen induces cytokine and collagen production in pancreatic stellate cells. Gut 58: 550–559. doi: 10.1136/gut.2008.154401
[22]
Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, et al. (1998) Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115: 421–432. doi: 10.1016/s0016-5085(98)70209-4
[23]
Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, et al. (2008) Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 68: 918–926. doi: 10.1158/0008-5472.can-07-5714
[24]
Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, et al. (2004) Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res 64: 3215–3222. doi: 10.1158/0008-5472.can-03-2464
[25]
Masamune A, Kikuta K, Watanabe T, Satoh K, Satoh A, et al. (2008) Pancreatic stellate cells express Toll-like receptors. J Gastroenterol 43: 352–362. doi: 10.1007/s00535-008-2162-0
[26]
Tripathi P, Tripathi AK, Kumar A, Ahmad R, Balapure AK, et al. (2009) Diagnostic and prognostic values of S-phase fraction and aneuploidy in patients with bone marrow aplasia. Indian J Hematol Blood Transfus 25: 10–16. doi: 10.1007/s12288-009-0003-9
[27]
Spector I, Honig H, Kawada N, Nagler A, Genin O, et al. (2010) Inhibition of pancreatic stellate cell activation by halofuginone prevents pancreatic xenograft tumor development. Pancreas 39: 1008–1015. doi: 10.1097/mpa.0b013e3181da8aa3
[28]
Daroqui CM, Ilarregui JM, Rubinstein N, Salatino M, Toscano MA, et al. (2007) Regulation of galectin-1 expression by transforming growth factor beta1 in metastatic mammary adenocarcinoma cells: implications for tumor-immune escape. Cancer Immunol Immunother 56: 491–499. doi: 10.1007/s00262-006-0208-9
[29]
Jiang X, Abiatari I, Kong B, Erkan M, De Oliveira T, et al. (2009) Pancreatic islet and stellate cells are the main sources of endocrine gland-derived vascular endothelial growth factor/prokineticin-1 in pancreatic cancer. Pancreatology 9: 165–172. doi: 10.1159/000178888
[30]
He J, Baum LG (2006) Galectin interactions with extracellular matrix and effects on cellular function. Methods Enzymol 417: 247–256. doi: 10.1016/s0076-6879(06)17017-2
[31]
Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, et al. (2007) The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A 104: 13134–13139. doi: 10.1073/pnas.0706017104
[32]
Thijssen VL, Postel R, Brandwijk RJ, Dings RP, Nesmelova I, et al. (2006) Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc Natl Acad Sci U S A 103: 15975–15980. doi: 10.1073/pnas.0603883103
[33]
Liu FT, Rabinovich GA (2005) Galectins as modulators of tumour progression. Nat Rev Cancer 5: 29–41. doi: 10.1038/nrc1527
[34]
Iacobuzio-Donahue CA, Ashfaq R, Maitra A, Adsay NV, Shen-Ong GL, et al. (2003) Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Cancer Res 63: 8614–8622.
[35]
Fitzner B, Walzel H, Sparmann G, Emmrich J, Liebe S, et al. (2005) Galectin-1 is an inductor of pancreatic stellate cell activation. Cell Signal 17: 1240–1247. doi: 10.1016/j.cellsig.2004.12.012
[36]
Apte MV, Pirola RC, Wilson JS (2006) Battle-scarred pancreas: role of alcohol and pancreatic stellate cells in pancreatic fibrosis. J Gastroenterol Hepatol 21 Suppl 3S97–S101. doi: 10.1111/j.1440-1746.2006.04587.x
[37]
Masamune A, Satoh M, Kikuta K, Suzuki N, Satoh K, et al. (2005) Ellagic acid blocks activation of pancreatic stellate cells. Biochem Pharmacol 70: 869–878. doi: 10.1016/j.bcp.2005.06.008
[38]
Masamune A, Watanabe T, Kikuta K, Shimosegawa T (2009) Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol 7: S48–54. doi: 10.1016/j.cgh.2009.07.038
Gerloff A, Singer MV, Feick P (2010) Beer and its non-alcoholic compounds: role in pancreatic exocrine secretion, alcoholic pancreatitis and pancreatic carcinoma. Int J Environ Res Public Health 7: 1093–1104. doi: 10.3390/ijerph7031093
[41]
Kikuta K, Masamune A, Watanabe T, Ariga H, Itoh H, et al. (2010) Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun 403: 380–384. doi: 10.1016/j.bbrc.2010.11.040
[42]
Jung EJ, Moon HG, Cho BI, Jeong CY, Joo YT, et al. (2007) Galectin-1 expression in cancer-associated stromal cells correlates tumor invasiveness and tumor progression in breast cancer. Int J Cancer 120: 2331–2338. doi: 10.1002/ijc.22434
[43]
Tang D, Wang D, Yuan Z, Xue X, Zhang Y, et al. (2013) Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J Cancer 132: 993–1003. doi: 10.1002/ijc.27715
[44]
Roda O, Ortiz-Zapater E, Martinez-Bosch N, Gutierrez-Gallego R, Vila-Perello M, et al.. (2009) Galectin-1 is a novel functional receptor for tissue plasminogen activator in pancreatic cancer.Gastroenterology 136: : 1379–1390, e1371–1375.
[45]
Grutzmann R, Pilarsky C, Ammerpohl O, Luttges J, Bohme A, et al. (2004) Gene expression profiling of microdissected pancreatic ductal carcinomas using high-density DNA microarrays. Neoplasia 6: 611–622. doi: 10.1593/neo.04295
[46]
Xue X, Lu Z, Tang D, Yao J, An Y, et al. (2011) Galectin-1 secreted by activated stellate cells in pancreatic ductal adenocarcinoma stroma promotes proliferation and invasion of pancreatic cancer cells: an in vitro study on the microenvironment of pancreatic ductal adenocarcinoma. Pancreas 40: 832–839. doi: 10.1097/mpa.0b013e318217945e
[47]
Chen R, Pan S, Ottenhof NA, de Wilde RF, Wolfgang CL, et al. (2012) Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma. Cancer Biol Ther 13: 899–907. doi: 10.4161/cbt.20842
[48]
Chung JC, Oh MJ, Choi SH, Bae CD (2008) Proteomic analysis to identify biomarker proteins in pancreatic ductal adenocarcinoma. ANZ J Surg 78: 245–251. doi: 10.1111/j.1445-2197.2008.04429.x
[49]
Qiu J, Gao HQ, Li BY, Shen L (2008) Proteomics investigation of protein expression changes in ouabain induced apoptosis in human umbilical vein endothelial cells. J Cell Biochem 104: 1054–1064. doi: 10.1002/jcb.21691
[50]
Thijssen VL, Barkan B, Shoji H, Aries IM, Mathieu V, et al. (2010) Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res 70: 6216–6224. doi: 10.1158/0008-5472.can-09-4150
[51]
Grassadonia A, Tinari N, Iurisci I, Piccolo E, Cumashi A, et al. (2004) 90K (Mac-2 BP) and galectins in tumor progression and metastasis. Glycoconj J 19: 551–556. doi: 10.1023/b:glyc.0000014085.00706.d4
[52]
Camby I, Belot N, Lefranc F, Sadeghi N, de Launoit Y, et al. (2002) Galectin-1 modulates human glioblastoma cell migration into the brain through modifications to the actin cytoskeleton and levels of expression of small GTPases. J Neuropathol Exp Neurol 61: 585–596.
[53]
Sioud M (2011) New insights into mesenchymal stromal cell-mediated T-cell suppression through galectins. Scand J Immunol 73: 79–84. doi: 10.1111/j.1365-3083.2010.02491.x
[54]
Kovacs-Solyom F, Blasko A, Fajka-Boja R, Katona RL, Vegh L, et al. (2010) Mechanism of tumor cell-induced T-cell apoptosis mediated by galectin-1. Immunol Lett 127: 108–118. doi: 10.1016/j.imlet.2009.10.003
[55]
Dings RP, Van Laar ES, Loren M, Webber J, Zhang Y, et al. (2010) Inhibiting tumor growth by targeting tumor vasculature with galectin-1 antagonist anginex conjugated to the cytotoxic acylfulvene, 6-hydroxylpropylacylfulvene. Bioconjug Chem 21: 20–27. doi: 10.1021/bc900287y
