Lewis antigen‑negative pancreatic cancer: An aggressive subgroup

Liu,Chen; Deng,Shengming; Jin,Kaizhou; Gong,Yitao; Cheng,He; Fan,Zhiyao; Qian,Yunzhen; Huang,Qiuyi; Ni,Quanxing; Luo,Guopei; Yu,Xianjun

doi:10.3892/ijo.2020.4989

Lewis antigen‑negative pancreatic cancer: An aggressive subgroup

Authors:
- Chen Liu
- Shengming Deng
- Kaizhou Jin
- Yitao Gong
- He Cheng
- Zhiyao Fan
- Yunzhen Qian
- Qiuyi Huang
- Quanxing Ni
- Guopei Luo
- Xianjun Yu
View Affiliations

Affiliations: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China, Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
Published online on: February 17, 2020 https://doi.org/10.3892/ijo.2020.4989
Pages: 900-908
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Carbohydrate antigen 19‑9 (CA19‑9) is the most important biomarker for pancreatic cancer. Approximately 5‑10% of individuals are Lewis antigen negative with scarce secretion of CA19‑9 and fucosylation deficiency. However, the characteristics of Lewis‑negative pancreatic cancer are unidentified. Clinicopathological characteristics of 853 patients with pancreatic cancer were examined. Pancreatic cancer cell lines were sequenced for Lewis status. Morphological and molecular features of pancreatic cancer cells were compared. Orthotopic animal modes were established. Lewis‑negative patients had poorer outcome (P<0.001), higher metastatic rate (P=0.004), lower CA19‑9 expression (P<0.001) and higher MUC16 expression (P<0.001) than Lewis‑positive patients. Lewis‑negative cells (CaPan‑1, MiaPaCa‑2 and Panc‑1) showed a shuttle shape with scarce pseudopods. Overall, Lewis‑negative cells had higher proliferation rate, higher migration ability, lower fucosylation, lower CA19‑9 expression and higher MUC16 expression than Lewis‑positive cells (BxPC‑3, SU8686, SW1990). Lewis‑negative cell line MiaPaCa‑2 corresponded to larger orthotopic tumor than Lewis‑positive cells SU8686. Potential proteoglycans were identified in Lewis‑positive cancer, including EGFR, HSPG2, ADAM17, GPC1, ITGA2, CD40, IL6ST and GGT1. Therefore, Lewis‑negative pancreatic cancer is an aggressive subgroup with special clinical and molecular features.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI
2	Ryan DP, Hong TS and Bardeesy N: Pancreatic adenocarcinoma. N Engl J Med. 371:2140–2141. 2014. View Article : Google Scholar : PubMed/NCBI
3	Long J, Luo GP, Xiao ZW, Liu ZQ, Guo M, Liu L, Liu C, Xu J, Gao YT, Zheng Y, et al: Cancer statistics: Current diagnosis and treatment of pancreatic cancer in Shanghai, China. Cancer Lett. 346:273–277. 2014. View Article : Google Scholar : PubMed/NCBI
4	Wallace DR, Spandidos DA, Tsatsakis A, Schweitzer A, Djordjevic V and Djordjevic AB: Potential interaction of cadmium chloride with pancreatic mitochondria: Implications for pancreatic cancer. Int J Mol Med. 44:145–156. 2019.PubMed/NCBI
5	Suzuki K, Takeuchi O, Suzuki Y and Kitagawa Y: Mechanisms of metformin's anti tumor activity against gemcitabine resistant pancreatic adenocarcinoma. Int J Oncol. 54:764–772. 2019.
6	Luo G, Liu C, Guo M, Long J, Liu Z, Xiao Z, Jin K, Cheng H, Lu Y, Ni Q, et al: CA19-9-Low&Lewis(+) pancreatic cancer: A unique subtype. Cancer Lett. 385:46–50. 2017. View Article : Google Scholar
7	Robert M, Jarlier M, Gourgou S, Desseigne F, Ychou M, Bouché O, Juzyna B, Conroy T and Bennouna J: Retrospective analysis of CA19-9 decrease in patients with metastatic pancreatic carcinoma treated with FOLFIRINOX or gemcitabine in a randomized phase III study (ACCORD11/PRODIGE4). Oncology. 93:367–376. 2017. View Article : Google Scholar : PubMed/NCBI
8	Humphris JL, Chang DK, Johns AL, Scarlett CJ, Pajic M, Jones MD, Colvin EK, Nagrial A, Chin VT, Chantrill LA, et al: NSW Pancreatic Cancer Network: The prognostic and predictive value of serum CA19.9 in pancreatic cancer. Ann Oncol. 23:1713–1722. 2012. View Article : Google Scholar : PubMed/NCBI
9	Luo G, Fan Z, Cheng H, Jin K, Guo M, Lu Y, Yang C, Fan K, Huang Q, Long J, et al: New observations on the utility of CA19-9 as a biomarker in Lewis negative patients with pancreatic cancer. Pancreatology. 18:971–976. 2018. View Article : Google Scholar : PubMed/NCBI
10	Guo M, Luo G, Lu R, Shi W, Cheng H, Lu Y, Jin K, Yang C, Wang Z, Long J, et al: Distribution of Lewis and Secretor polymorphisms and corresponding CA19-9 antigen expression in a Chinese population. FEBS Open Bio. 7:1660–1671. 2017. View Article : Google Scholar : PubMed/NCBI
11	Luo G, Liu C, Guo M, Cheng H, Lu Y, Jin K, Liu L, Long J, Xu J, Lu R, et al: Potential biomarkers in Lewis negative patients with pancreatic cancer. Ann Surg. 265:800–805. 2017. View Article : Google Scholar : PubMed/NCBI
12	Gao HF, Wang QY, Zhang K, Chen LY, Cheng CS, Chen H, Meng ZQ, Zhou SM and Chen Z: Overexpressed N-fucosylation on the cell surface driven by FUT3, 5, and 6 promotes cell motilities in metastatic pancreatic cancer cell lines. Biochem Biophys Res Commun. 511:482–489. 2019. View Article : Google Scholar : PubMed/NCBI
13	Luo G, Guo M, Jin K, Liu Z, Liu C, Cheng H, Lu Y, Long J, Liu L, Xu J, et al: Optimize CA19-9 in detecting pancreatic cancer by Lewis and Secretor genotyping. Pancreatology. 16:1057–1062. 2016. View Article : Google Scholar : PubMed/NCBI
14	Wiśniewski JR, Zougman A, Nagaraj N and Mann M: Universal sample preparation method for proteome analysis. Nat Methods. 6:359–362. 2009. View Article : Google Scholar
15	Luo G, Xiao Z, Long J, Liu Z, Liu L, Liu C, Xu J, Ni Q and Yu X: CA125 is superior to CA19-9 in predicting the resectability of pancreatic cancer. J Gastrointest Surg. 17:2092–2098. 2013. View Article : Google Scholar : PubMed/NCBI
16	Tsai S, George B, Wittmann D, Ritch PS, Krepline AN, Aldakkak M, Barnes CA, Christians KK, Dua K, Griffin M, et al: Importance of normalization of CA19-9 levels following neoadjuvant therapy in patients with localized pancreatic cancer. Ann Surg. Oct 11–2018.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
17	Takada A, Ohmori K, Yoneda T, Tsuyuoka K, Hasegawa A, Kiso M and Kannagi R: Contribution of carbohydrate antigens sialyl Lewis A and sialyl Lewis X to adhesion of human cancer cells to vascular endothelium. Cancer Res. 53:354–361. 1993.PubMed/NCBI
18	Engle DD, Tiriac H, Rivera KD, Pommier A, Whalen S, Oni TE, Alagesan B, Lee EJ, Yao MA, Lucito MS, et al: The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. Science. 364:1156–1162. 2019. View Article : Google Scholar : PubMed/NCBI
19	Gebauer F, Wicklein D, Stübke K, Nehmann N, Schmidt A, Salamon J, Peldschus K, Nentwich MF, Adam G, Tolstonog G, et al: Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp–/rag2– mice. Gut. 62:741–750. 2013. View Article : Google Scholar
20	Hamada E, Taniguchi T, Baba S and Maekawa M: Investigation of unexpected serum CA19-9 elevation in Lewis-negative cancer patients. Ann Clin Biochem. 49:266–272. 2012. View Article : Google Scholar : PubMed/NCBI
21	Padró M, Cobler L, Garrido M and de Bolós C: Down-regulation of FUT3 and FUT5 by shRNA alters Lewis antigens expression and reduces the adhesion capacities of gastric cancer cells. Biochim Biophys Acta. 1810:1141–1149. 2011. View Article : Google Scholar : PubMed/NCBI
22	Orntoft TF, Vestergaard EM, Holmes E, Jakobsen JS, Grunnet N, Mortensen M, Johnson P, Bross P, Gregersen N, Skorstengaard K, et al: Influence of Lewis alpha1-3/4-L-fucos-yltransferase (FUT3) gene mutations on enzyme activity, erythrocyte phenotyping, and circulating tumor marker sialyl-Lewis a levels. J Biol Chem. 271:32260–32268. 1996. View Article : Google Scholar : PubMed/NCBI
23	Weston BW, Hiller KM, Mayben JP, Manousos GA, Bendt KM, Liu R and Cusack JC Jr: Expression of human alpha(1,3)fucosyltransferase antisense sequences inhibits selectin-mediated adhesion and liver metastasis of colon carcinoma cells. Cancer Res. 59:2127–2135. 1999.PubMed/NCBI
24	Fan K, Yang C, Fan Z, Huang Q, Zhang Y, Cheng H, Jin K, Lu Y, Wang Z, Luo G, et al: MUC16 C terminal-induced secretion of tumor-derived IL-6 contributes to tumor-associated Treg enrichment in pancreatic cancer. Cancer Lett. 418:167–175. 2018. View Article : Google Scholar : PubMed/NCBI
25	Fleming ND, Cass I, Walsh CS, Karlan BY and Li AJ: CA125 surveillance increases optimal resectability at secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecol Oncol. 121:249–252. 2011. View Article : Google Scholar : PubMed/NCBI
26	Akita K, Tanaka M, Tanida S, Mori Y, Toda M and Nakada H: CA125/MUC16 interacts with Src family kinases, and over-expression of its C-terminal fragment in human epithelial cancer cells reduces cell-cell adhesion. Eur J Cell Biol. 92:257–263. 2013. View Article : Google Scholar : PubMed/NCBI