Additive clinical impact of epidermal growth factor receptor and podocalyxin-like protein expression in pancreatic and periampullary adenocarcinomas.
Adenocarcinoma
/ metabolism
Ampulla of Vater
/ metabolism
Biomarkers, Tumor
/ metabolism
ErbB Receptors
/ metabolism
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Pancreatic Neoplasms
/ metabolism
Pancreaticoduodenectomy
/ mortality
Prognosis
Retrospective Studies
Sialoglycoproteins
/ metabolism
Survival Rate
Tumor Cells, Cultured
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
25 06 2020
25 06 2020
Historique:
received:
18
03
2019
accepted:
03
06
2020
entrez:
27
6
2020
pubmed:
27
6
2020
medline:
15
12
2020
Statut:
epublish
Résumé
The outcome of periampullary adenocarcinomas remains poor with few treatment options. Podocalyxin-like protein (PODXL) is an anti-adhesive protein, the high expression of which has been shown to confer a poor prognosis in numerous malignancies. A correlation and adverse prognostic synergy between PODXL and the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer. Here, we investigated whether this also applies to periampullary adenocarcinomas. We analyzed the immunohistochemical expression of PODXL and EGFR in tissue microarrays with tumors from two patient cohorts; (Cohort 1, n = 175) and (Cohort 2, n = 189). The effect of TGF-β-induced expression and siRNA-mediated knockdown of PODXL and EGFR, were investigated in pancreatic cancer cells (PANC-1) in vitro. We found a correlation between PODXL and EGFR in these cancers, and a synergistic adverse effect on survival. Furthermore, silencing PODXL in pancreatic cancer cells resulted in the down-regulation of EGFR, but not vice versa. Consequently, these findings suggest a functional link between PODXL and EGFR, and the potential combined utility as biomarkers possibly improving patient stratification. Further studies examining the mechanistic basis underlying these observations may open new avenues of targeted treatment options for subsets of patients affected by these particularly aggressive cancers.
Identifiants
pubmed: 32587323
doi: 10.1038/s41598-020-67187-z
pii: 10.1038/s41598-020-67187-z
pmc: PMC7316735
doi:
Substances chimiques
Biomarkers, Tumor
0
Sialoglycoproteins
0
podocalyxin
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10373Références
Westgaard, A. et al. Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. BMC cancer 8, 170, https://doi.org/10.1186/1471-2407-8-170 (2008).
doi: 10.1186/1471-2407-8-170
pubmed: 18547417
pmcid: 2430209
Bronsert, P. et al. Intestinal-type of differentiation predicts favourable overall survival: confirmatory clinicopathological analysis of 198 periampullary adenocarcinomas of pancreatic, biliary, ampullary and duodenal origin. BMC cancer 13, 428, https://doi.org/10.1186/1471-2407-13-428 (2013).
doi: 10.1186/1471-2407-13-428
pubmed: 24053229
pmcid: 3849372
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2016. CA: a cancer journal for clinicians 66, 7–30, https://doi.org/10.3322/caac.21332 (2016).
doi: 10.3322/caac.21332
Herreros-Villanueva, M., Hijona, E., Cosme, A. & Bujanda, L. Adjuvant and neoadjuvant treatment in pancreatic cancer. World journal of gastroenterology 18, 1565–1572, https://doi.org/10.3748/wjg.v18.i14.1565 (2012).
doi: 10.3748/wjg.v18.i14.1565
pubmed: 22529684
pmcid: 3325521
Kerjaschki, D., Sharkey, D. J. & Farquhar, M. G. Identification and characterization of podocalyxin–the major sialoprotein of the renal glomerular epithelial cell. The Journal of cell biology 98, 1591–1596 (1984).
doi: 10.1083/jcb.98.4.1591
Doyonnas, R. et al. Anuria, omphalocele, and perinatal lethality in mice lacking the CD34-related protein podocalyxin. The Journal of experimental medicine 194, 13–27 (2001).
doi: 10.1084/jem.194.1.13
Horvat, R., Hovorka, A., Dekan, G., Poczewski, H. & Kerjaschki, D. Endothelial cell membranes contain podocalyxin–the major sialoprotein of visceral glomerular epithelial cells. The Journal of cell biology 102, 484–491 (1986).
doi: 10.1083/jcb.102.2.484
Doyonnas, R. et al. Podocalyxin is a CD34-related marker of murine hematopoietic stem cells and embryonic erythroid cells. Blood 105, 4170–4178, https://doi.org/10.1182/blood-2004-10-4077 (2005).
doi: 10.1182/blood-2004-10-4077
pubmed: 15701716
McNagny, K. M. et al. Thrombomucin, a novel cell surface protein that defines thrombocytes and multipotent hematopoietic progenitors. The Journal of cell biology 138, 1395–1407 (1997).
doi: 10.1083/jcb.138.6.1395
Heby, M., Elebro, J., Nodin, B., Jirstrom, K. & Eberhard, J. Prognostic and predictive significance of podocalyxin-like protein expression in pancreatic and periampullary adenocarcinoma. BMC clinical pathology 15, 10, https://doi.org/10.1186/s12907-015-0009-1 (2015).
doi: 10.1186/s12907-015-0009-1
pubmed: 26028992
pmcid: 4449563
Somasiri, A. et al. Overexpression of the anti-adhesin podocalyxin is an independent predictor of breast cancer progression. Cancer research 64, 5068–5073, https://doi.org/10.1158/0008-5472.CAN-04-0240 (2004).
doi: 10.1158/0008-5472.CAN-04-0240
pubmed: 15289306
Larsson, A. et al. Overexpression of podocalyxin-like protein is an independent factor of poor prognosis in colorectal cancer. British journal of cancer 105, 666–672, https://doi.org/10.1038/bjc.2011.295 (2011).
doi: 10.1038/bjc.2011.295
pubmed: 21829192
pmcid: 3188928
Larsson, A. H. et al. Validation of podocalyxin-like protein as a biomarker of poor prognosis in colorectal cancer. BMC Cancer 12, 282, https://doi.org/10.1186/1471-2407-12-282 (2012).
doi: 10.1186/1471-2407-12-282
pubmed: 22769594
pmcid: 3492217
Larsson, A. H. et al. Podocalyxin-like protein expression in primary colorectal cancer and synchronous lymph node metastases. Diagnostic pathology 8, 109, https://doi.org/10.1186/1746-1596-8-109 (2013).
doi: 10.1186/1746-1596-8-109
pubmed: 23819542
pmcid: 3751142
Kaprio, T. et al. Podocalyxin is a marker of poor prognosis in colorectal cancer. BMC Cancer 14, 493, https://doi.org/10.1186/1471-2407-14-493 (2014).
doi: 10.1186/1471-2407-14-493
pubmed: 25004863
pmcid: 4226963
Cipollone, J. A. et al. The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma. Clinical & experimental metastasis 29, 239–252, https://doi.org/10.1007/s10585-011-9446-0 (2012).
doi: 10.1007/s10585-011-9446-0
Boman, K. et al. Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer. British journal of cancer 108, 2321–2328, https://doi.org/10.1038/bjc.2013.215 (2013).
doi: 10.1038/bjc.2013.215
pubmed: 23652315
pmcid: 3681027
Binder, Z. A. et al. Podocalyxin-like protein is expressed in glioblastoma multiforme stem-like cells and is associated with poor outcome. PloS one 8, e75945, https://doi.org/10.1371/journal.pone.0075945 (2013).
doi: 10.1371/journal.pone.0075945
pubmed: 24146797
pmcid: 3797817
Meng, X., Ezzati, P. & Wilkins, J. A. Requirement of podocalyxin in TGF-beta induced epithelial mesenchymal transition. PloS one 6, e18715, https://doi.org/10.1371/journal.pone.0018715 (2011).
doi: 10.1371/journal.pone.0018715
pubmed: 21533279
pmcid: 3075272
Miettinen, P. J., Ebner, R., Lopez, A. R. & Derynck, R. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. The Journal of cell biology 127, 2021–2036, https://doi.org/10.1083/jcb.127.6.2021 (1994).
doi: 10.1083/jcb.127.6.2021
pubmed: 7806579
Arteaga, C. L. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 19, 32S–40S (2001).
Oliveira-Cunha, M., Newman, W. G. & Siriwardena, A. K. Epidermal growth factor receptor in pancreatic cancer. Cancers 3, 1513–1526, https://doi.org/10.3390/cancers3021513 (2011).
doi: 10.3390/cancers3021513
pubmed: 24212772
pmcid: 3757375
Xiong, H. Q. & Abbruzzese, J. L. Epidermal growth factor receptor-targeted therapy for pancreatic cancer. Seminars in oncology 29, 31–37, https://doi.org/10.1053/sonc.2002.35645 (2002).
doi: 10.1053/sonc.2002.35645
pubmed: 12422311
Ueda, S. et al. The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas 29, e1–8 (2004).
doi: 10.1097/00006676-200407000-00061
Larsson, A. H. et al. Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer. Journal of translational medicine 14, 128, https://doi.org/10.1186/s12967-016-0882-0 (2016).
doi: 10.1186/s12967-016-0882-0
pubmed: 27160084
pmcid: 4862047
Elebro, J. & Jirstrom, K. Use of a standardized diagnostic approach improves the prognostic information of histopathologic factors in pancreatic and periampullary adenocarcinoma. Diagnostic Pathology 9, 80, https://doi.org/10.1186/1746-1596-9-80 (2014).
doi: 10.1186/1746-1596-9-80
pubmed: 24731283
pmcid: 3999361
Fristedt, R. et al. Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis. PloS one 9, e112728, https://doi.org/10.1371/journal.pone.0112728 (2014).
doi: 10.1371/journal.pone.0112728
pubmed: 25397670
pmcid: 4232506
Elebro, J. et al. Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1, 2 and 3 in Periampullary Adenocarcinoma. PloS one 11, e0153533, https://doi.org/10.1371/journal.pone.0153533 (2016).
doi: 10.1371/journal.pone.0153533
pubmed: 27070783
pmcid: 4829175
Elebro, J. et al. Prognostic and treatment predictive significance of SATB1 and SATB2 expression in pancreatic and periampullary adenocarcinoma. Journal of translational medicine 12, 289, https://doi.org/10.1186/s12967-014-0289-8 (2014).
doi: 10.1186/s12967-014-0289-8
pubmed: 25323550
pmcid: 4232660
Saukkonen, K. et al. Podocalyxin Is a Marker of Poor Prognosis in Pancreatic Ductal Adenocarcinoma. PloS one 10, e0129012, https://doi.org/10.1371/journal.pone.0129012 (2015).
doi: 10.1371/journal.pone.0129012
pubmed: 26053486
pmcid: 4459962
Saukkonen, K. et al. PROX1 and beta-catenin are prognostic markers in pancreatic ductal adenocarcinoma. BMC cancer 16, 472, https://doi.org/10.1186/s12885-016-2497-5 (2016).
doi: 10.1186/s12885-016-2497-5
pubmed: 27411302
pmcid: 4944261
Ruschoff, J. et al. HER2 testing in gastric cancer: a practical approach. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 25, 637–650, https://doi.org/10.1038/modpathol.2011.198 (2012).
doi: 10.1038/modpathol.2011.198
Karnevi, E. et al. Translational study reveals a two-faced role of RBM3 in pancreatic cancer and suggests its potential value as a biomarker for improved patient stratification. Oncotarget 9, 6188–6200, https://doi.org/10.18632/oncotarget.23486 (2018).
doi: 10.18632/oncotarget.23486
pubmed: 29464064
Moutasim, K. A., Nystrom, M. L. & Thomas, G. J. Cell migration and invasion assays. Methods Mol Biol 731, 333–343, https://doi.org/10.1007/978-1-61779-080-5_27 (2011).
doi: 10.1007/978-1-61779-080-5_27
pubmed: 21516419
Froeling, F. E., Marshall, J. F. & Kocher, H. M. Pancreatic cancer organotypic cultures. Journal of biotechnology 148, 16–23, https://doi.org/10.1016/j.jbiotec.2010.01.008 (2010).
doi: 10.1016/j.jbiotec.2010.01.008
pubmed: 20083148
Frose, J. et al. Epithelial-Mesenchymal Transition Induces Podocalyxin to Promote Extravasation via Ezrin Signaling. Cell reports 24, 962–972, https://doi.org/10.1016/j.celrep.2018.06.092 (2018).
doi: 10.1016/j.celrep.2018.06.092
pubmed: 30044991
pmcid: 6181240
Nakajima, S. et al. N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clinical cancer research: an official journal of the American Association for Cancer Research 10, 4125–4133, https://doi.org/10.1158/1078-0432.CCR-0578-03 (2004).
doi: 10.1158/1078-0432.CCR-0578-03
Pickup, M., Novitskiy, S. & Moses, H. L. The roles of TGFbeta in the tumour microenvironment. Nature reviews. Cancer 13, 788–799, https://doi.org/10.1038/nrc3603 (2013).
doi: 10.1038/nrc3603
pubmed: 24132110
pmcid: 4025940
Derynck, R., Akhurst, R. J. & Balmain, A. TGF-beta signaling in tumor suppression and cancer progression. Nature genetics 29, 117–129, https://doi.org/10.1038/ng1001-117 (2001).
doi: 10.1038/ng1001-117
pubmed: 11586292
Hahn, S. A. et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353, https://doi.org/10.1126/science.271.5247.350 (1996).
doi: 10.1126/science.271.5247.350
pubmed: 8553070
Javle, M. et al. Biomarkers of TGF-beta signaling pathway and prognosis of pancreatic cancer. PloS one 9, e85942, https://doi.org/10.1371/journal.pone.0085942 (2014).
doi: 10.1371/journal.pone.0085942
pubmed: 24465802
pmcid: 3896410
Barr, S. et al. Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clinical & experimental metastasis 25, 685–693, https://doi.org/10.1007/s10585-007-9121-7 (2008).
doi: 10.1007/s10585-007-9121-7
Li, Y., Li, J., Straight, S. W. & Kershaw, D. B. PDZ domain-mediated interaction of rabbit podocalyxin and Na(+)/H(+) exchange regulatory factor-2. American journal of physiology. Renal physiology 282, F1129–1139, https://doi.org/10.1152/ajprenal.00131.2001 (2002).
doi: 10.1152/ajprenal.00131.2001
pubmed: 11997330
Lazar, C. S., Cresson, C. M., Lauffenburger, D. A. & Gill, G. N. The Na+/H+ exchanger regulatory factor stabilizes epidermal growth factor receptors at the cell surface. Molecular biology of the cell 15, 5470–5480, https://doi.org/10.1091/mbc.E04-03-0239 (2004).
doi: 10.1091/mbc.E04-03-0239
pubmed: 15469991
pmcid: 532026
Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England journal of medicine 350, 2129–2139, https://doi.org/10.1056/NEJMoa040938 (2004).
doi: 10.1056/NEJMoa040938
pubmed: 15118073
Moore, M. 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. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 25, 1960–1966, https://doi.org/10.1200/JCO.2006.07.9525 (2007).
doi: 10.1200/JCO.2006.07.9525
Izumchenko, E. et al. The TGFbeta-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. Cancer research 74, 3995–4005, https://doi.org/10.1158/0008-5472.CAN-14-0110 (2014).
doi: 10.1158/0008-5472.CAN-14-0110
pubmed: 24830724
pmcid: 4122100
Deer, E. L. et al. Phenotype and genotype of pancreatic cancer cell lines. Pancreas 39, 425–435, https://doi.org/10.1097/MPA.0b013e3181c15963 (2010).
doi: 10.1097/MPA.0b013e3181c15963
pubmed: 20418756
pmcid: 2860631
Luttges, J. et al. The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium. Cancer 85, 1703–1710 (1999).
doi: 10.1002/(SICI)1097-0142(19990415)85:8<1703::AID-CNCR9>3.0.CO;2-R
Torhorst, J. et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints. The American journal of pathology 159, 2249–2256, https://doi.org/10.1016/S0002-9440(10)63075-1 (2001).
doi: 10.1016/S0002-9440(10)63075-1
pubmed: 11733374
pmcid: 1850582