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01-12-2018 | Pancreatic Tumors

Tumor-Infiltrating Platelets Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma

Authors: Shi-Rong Zhang, M.Med, Lie Yao, MD, PhD, Wen-Quan Wang, MD, PhD, Jin-Zhi Xu, M.Med, Hua-Xiang Xu, MD, Wei Jin, PhD, He-Li Gao, MD, PhD, Chun-Tao Wu, MD, Zi-Hao Qi, MD, Hao Li, MD, PhD, Shuo Li, MD, Quan-Xing Ni, MD, Xian-Jun Yu, MD, PhD, De-Liang Fu, MD, PhD, Liang Liu, MD, PhD

Published in: Annals of Surgical Oncology | Issue 13/2018

Abstract

Background

Platelets are believed to promote tumor growth and metastasis in several tumor types. The prognostic role of blood platelets in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the prognostic value of tumor-infiltrating platelets (TIPs) remains unknown.

Methods

A total of 303 patients who underwent curative pancreatectomy for PDAC were enrolled from two independent centers in China and divided into three cohorts. Paired preoperative blood samples and surgical specimens from all patients were analyzed. The correlations between patient outcomes and preoperative blood platelet counts and the presence of TIPs, respectively, were analyzed. TIPs were identified by immunohistochemical staining of CD42b. Prognostic accuracy was estimated by concordance index (C-index) and Akaike information criterion (AIC).

Results

TIPs, but not preoperative blood platelet counts, were associated with overall survival (OS; all P < 0.001) and recurrence-free survival (RFS; all P < 0.001) in the training, testing, and validation sets. Positive CD42b expression predicted poor postsurgical survival. Incorporation of TIPs improved the predictive accuracy of the 8th edition American Joint Committee on Cancer (AJCC) tumor–node–metastasis (TNM) staging system for OS in each of the three cohorts (C-index: 0.7164, 0.7569, and 0.7050, respectively; AIC: 472, 386, and 1019, respectively). The new predictor system was validated by incorporating TIPs with the 7th edition AJCC TNM staging system (C-index: 0.7052, 0.7623, and 0.7157; AIC: 476, 386, and 1015).

Conclusion

TIPs were an independent prognostic factor that could be incorporated into the AJCC TNM staging system to refine risk stratification and predict surgical outcomes of patients with PDAC.

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Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.CrossRef

Long J, Luo GP, Xiao ZW, Liu ZQ, Guo M, Liu L, et al. Cancer statistics: current diagnosis and treatment of pancreatic cancer in Shanghai, China. Cancer Lett. 2014;346:273–7.CrossRef

Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21.CrossRef

Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388:73–85.CrossRef

Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482–94.CrossRef

Li N. Platelets in cancer metastasis: to help the “villain” to do evil. Int J Cancer. 2016;138:2078–87.CrossRef

Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science. 2010;328:562–4.CrossRef

Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res. 1999;59:1295–300.PubMed

Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood. 2005;105:178–85.CrossRef

10.

Schumacher D, Strilic B, Sivaraj KK, Wettschureck N, Offermanns S. Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell. 2013;24:130–7.CrossRef

11.

Wang H, Gao J, Bai M, Liu R, Li H, Deng T, et al. The pretreatment platelet and plasma fibrinogen level correlate with tumor progression and metastasis in patients with pancreatic cancer. Platelets. 2014;25:382–7.CrossRef

12.

Shirai Y, Shiba H, Haruki K, Horiuchi T, Saito N, Fujiwara Y, et al. Preoperative platelet-to-albumin ratio predicts prognosis of patients with pancreatic ductal adenocarcinoma after pancreatic resection. Anticancer Res. 2017;37:787–93.CrossRef

13.

Miyamoto R, Oda T, Hashimoto S, Kurokawa T, Kohno K, Akashi Y, et al. Platelet × CRP multiplier value as an indicator of poor prognosis in patients with resectable pancreatic cancer. Pancreas. 2017;46:35–41.CrossRef

14.

Chadha AS, Kocak-Uzel E, Das P, Minsky BD, Delclos ME, Mahmood U, et al. Paraneoplastic thrombocytosis independently predicts poor prognosis in patients with locally advanced pancreatic cancer. Acta Oncol. 2015;54:971–8.CrossRef

15.

Aliustaoglu M, Bilici A, Seker M, Dane F, Gocun M, Konya V, et al. The association of pre-treatment peripheral blood markers with survival in patients with pancreatic cancer. Hepatogastroenterology. 2010;57:640–5.PubMed

16.

Xiao Y, Xie H, Xie Z, Shao Z, Chen W, Qin G, et al. Kinetics of postdiagnosis platelet count with overall survival of pancreatic cancer: a counting process approach. Cancer Med. 2016;5:881–7.CrossRef

17.

Schwarz RE. Platelet counts and prognosis of pancreatic cancer. Lancet. 1999;353:2158–9.CrossRef

18.

Miyashita T, Tajima H, Makino I, Nakagawara H, Kitagawa H, Fushida S, et al. Metastasis-promoting role of extravasated platelet activation in tumor. J Surg Res. 2015;193:289–94.CrossRef

19.

Saito H, Fushida S, Miyashita T, Oyama K, Yamaguchi T, Tsukada T, et al. Potential of extravasated platelet aggregation as a surrogate marker for overall survival in patients with advanced gastric cancer treated with preoperative docetaxel, cisplatin and S-1: a retrospective observational study. BMC Cancer. 2017;17:294.CrossRef

20.

Ishikawa S, Miyashita T, Inokuchi M, Hayashi H, Oyama K, Tajima H, et al. Platelets surrounding primary tumor cells are related to chemoresistance. Oncol Rep. 2016;36:787–94.CrossRef

21.

Haemmerle M, Bottsford-Miller J, Pradeep S, Taylor ML, Choi HJ, Hansen JM, et al. FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal. J Clin Invest. 2016;126:1885–96.CrossRef

22.

Wang WQ, Liu L, Xu HX, Wu CT, Xiang JF, Xu J, et al. Infiltrating immune cells and gene mutations in pancreatic ductal adenocarcinoma. Br J Surg. 2016;103:1189–99.CrossRef

23.

Wang WQ, Liu L, Xu HX, Luo GP, Chen T, Wu CT, et al. Intratumoral α-SMA enhances the prognostic potency of CD34 associated with maintenance of microvessel integrity in hepatocellular carcinoma and pancreatic cancer. PLoS One. 2013;8:e71189.CrossRef

24.

Wang WQ, Liu L, Xu HX, Sun HC, Wu CT, Zhu XD, et al. The combination of HTATIP2 expression and microvessel density predicts converse survival of hepatocellular carcinoma with or without sorafenib. Oncotarget. 2014;5:3895–906.PubMedPubMedCentral

25.

Yan M, Jurasz P. The role of platelets in the tumor microenvironment: From solid tumors to leukemia. Biochim Biophys Acta. 2016;1863:392–400.CrossRef

26.

Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford-Miller J, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med. 2012;366:610–8.CrossRef

27.

Georgiadou D, Sergentanis TN, Sakellariou S, Filippakis GM, Zagouri F, Vlachodimitropoulos D, et al. VEGF and Id-1 in pancreatic adenocarcinoma: prognostic significance and impact on angiogenesis. Eur J Surg Oncol. 2014;40:1331–7.CrossRef

28.

Stellos K, Langer H, Daub K, Schoenberger T, Gauss A, Geisler T, et al. Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34 + cells to endothelial progenitor cells. Circulation. 2008;117:206–15.CrossRef

29.

Li R, Ren M, Chen N, Luo M, Deng X, Xia J, et al. Presence of intratumoral platelets is associated with tumor vessel structure and metastasis. BMC Cancer. 2014;14:167.CrossRef

30.

Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475:226–30.CrossRef

31.

Ye LY, Zhang Q, Bai XL, Pankaj P, Hu QD, Liang TB. Hypoxia-inducible factor 1α expression and its clinical significance in pancreatic cancer: a meta-analysis. Pancreatology. 2014;14:391–7.CrossRef

32.

Cai X, Ding H, Liu Y, Pan G, Li Q, Yang Z, et al. Expression of HMGB2 indicates worse survival of patients and is required for the maintenance of Warburg effect in pancreatic cancer. Acta Biochim Biophys Sin (Shanghai). 2017;49:119–27.CrossRef

33.

Qi C, Li B, Guo S, Wei B, Shao C, Li J, et al. P-Selectin-Mediated Adhesion between Platelets and Tumor Cells Promotes Intestinal Tumorigenesis in Apc(Min/+) Mice. Int J Biol Sci. 2015;11:679–87.CrossRef

34.

Yu LX, Yan L, Yang W, Wu FQ, Ling Y, Chen SZ, et al. Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein. Nat Commun. 2014;5:5256.CrossRef

35.

Jurasz P, Alonso-Escolano D, Radomski MW. Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br J Pharmacol. 2004;143:819–26.CrossRef

36.

Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer. 2011;11:123–34.CrossRef

37.

Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20:576–90.CrossRef

38.

Krebs AM, Mitschke J, Lasierra LM, Schmalhofer O, Boerries M, Busch H, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol. 2017;19:518–29.CrossRef

39.

Bertozzi CC, Hess PR, Kahn ML. Platelets: covert regulators of lymphatic development. Arterioscler Thromb Vasc Biol. 2010;30:2368–71.CrossRef

Title: Tumor-Infiltrating Platelets Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma
Authors: Shi-Rong Zhang, M.Med
Lie Yao, MD, PhD
Wen-Quan Wang, MD, PhD
Jin-Zhi Xu, M.Med
Hua-Xiang Xu, MD
Wei Jin, PhD
He-Li Gao, MD, PhD
Chun-Tao Wu, MD
Zi-Hao Qi, MD
Hao Li, MD, PhD
Shuo Li, MD
Quan-Xing Ni, MD
Xian-Jun Yu, MD, PhD
De-Liang Fu, MD, PhD
Liang Liu, MD, PhD
Publication date: 01-12-2018
Publisher: Springer International Publishing
Published in: Annals of Surgical Oncology / Issue 13/2018
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-018-6727-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Tumor-Infiltrating Platelets Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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