Skip to main content

Advertisement

SpringerLink
Log in

The prognostic value and pathobiological significance of Glasgow microenvironment score in gastric cancer

  • Original Article – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the prognostic value and pathobiological significance of Glasgow microenvironment score (GMS), a parameter based on tumor stroma percentage and inflammatory cell infiltration, in gastric cancer.

Methods

A total of 225 cases of gastric cancer were histologically reviewed, and GMS was evaluated for each case. The association between GMS and patients’ survival was investigated. Then the relationship between GMS and mismatch repair (MMR) status, Epstein–Barr virus (EBV) infection were determined using immunohistochemistry (IHC) and in situ hybridization, and the expression of PD1/PD-L1 was examined. Furthermore, the amount of cancer-associated fibroblasts (CAFs), the content and maturity of collagen components were detected using IHC, Picrosirius Red staining and second harmonic generation imaging.

Results

GMS was significantly associated with clinical outcomes of gastric cancer, and multivariate analysis indicated that GMS was an independent factor (HR 1.725, P = 0.002). Low GMS was a manifestation of better prognosis and inflammatory tumor microenvironment, which was related to MMR deficiency (P = 0.042) and EBV infection (P = 0.032), and within this microenvironment, expression of PD-L1 in carcinoma cells (P = 0.030) or in inflammatory cells (P = 0.029) was significantly higher. In contrast, high GMS linked to a poorer survival and desmoplastic stroma, in which there existed markedly increased CAFs and collagen deposition.

Conclusion

GMS can serve as a useful prognostic factor for gastric cancer, and according to GMS, the tumor microenvironment in this cancer type may be partially classified as inflammatory or desmoplastic microenvironment that possesses different pathobiological features.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Alexander J, Cukierman E (2016) Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions. Curr Opin Cell Biol 42:80–93

    Article  CAS  PubMed  Google Scholar 

  • Alsina M, Moehler M, Hierro C, Guardeño R, Tabernero J (2016) Immunotherapy for gastric cancer: a focus on immune checkpoints. Target Oncol 11:469–477

    Article  PubMed  Google Scholar 

  • Baldan V, Griffiths R, Hawkins RE, Gilham DE (2015) Efficient and reproducible generation of tumour-infiltrating lymphocytes for renal cell carcinoma. Br J Cancer 112:1510–1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berruti A, Piovesan A, Torta M, Raucci CA, Gorzegno G, Paccotti P, Dogliotti L, Angeli A (1996) Biochemical evaluation of bone turnover in cancer patients with bone metastases: relationship with radiograph appearances and disease extension. Br J Cancer 73:1581–1587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calon A, Tauriello DV, Batlle E (2014) TGF-beta in CAF-mediated tumor growth and metastasis. Semin Cancer Biol 25:15–22

    Article  CAS  PubMed  Google Scholar 

  • Chetty R (2012) Gastrointestinal cancers accompanied by a dense lymphoid component: an overview with special reference to gastric and colonic medullary and lymphoepithelioma-like carcinomas. J Clin Pathol 65:1062–1065

    Article  PubMed  Google Scholar 

  • Conklin MW, Keely PJ (2012) Why the stroma matters in breast cancer: insights into breast cancer patient outcomes through the examination of stromal biomarkers. Cell Adh Migr 6:249–260

    Article  PubMed  PubMed Central  Google Scholar 

  • Dieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, Goubar A (2015) Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol 26:1698–1704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drifka CR, Tod J, Loeffler AG, Liu Y, Thomas GJ, Eliceiri KW, Kao WJ (2015) Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis. Mod Pathol 28:1470–1480

    Article  CAS  PubMed  Google Scholar 

  • Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (2009) AJCC Cancer Staging Manual. Springer, New York

    Google Scholar 

  • Egeblad M, Rasch M, Weaver VM (2010) Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol 22: 697–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fearon DT (2014) The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer. Immunol Res 2:187–193

    CAS  Google Scholar 

  • Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer. http://globocan.iarc.fr. Accessed 20 Dec 2016

  • Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grossman M, Benchetrit N, Zhuravlev A, Afik R, Bassat E, Solomonov I, Yarden Y, Sagi I (2016) Tumor cell invasion can be blocked by modulators of collagen fibril alignment that control assembly of the extracellular matrix. Cancer Res 76:4249–4258

    Article  CAS  PubMed  Google Scholar 

  • Gujam FJ, Edwards J, Mohammed ZM, Going JJ, McMillan DC (2014) The relationship between the tumour stroma percentage, clinicopathological characteristics and outcome in patients with operable ductal breast cancer. Br J Cancer 111:157–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harper J, Sainson RC (2014) Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin Cancer Biol 25:69–77

    Article  CAS  PubMed  Google Scholar 

  • Hulmes DJ (2002) Building collagen molecules, fibrils, and suprafibrillar structures. J Struct Biol 137:2–10

    Article  CAS  PubMed  Google Scholar 

  • Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252

    Article  CAS  PubMed  Google Scholar 

  • Kang BW, Seo AN, Yoon S, Bae HI, Jeon SW, Kwon OK (2016) Prognostic value of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer. Ann Oncol 27:494–501

    Article  CAS  PubMed  Google Scholar 

  • Kauppila S, Stenback F, Risteli J, Jukkola A, Risteli L (1998) Aberrant type I and type III collagen gene expression in human breast cancer in vivo. J Pathol 186:262–268

    Article  CAS  PubMed  Google Scholar 

  • Keikhosravi A, Bredfeldt JS, Sagar AK, Eliceiri KW (2014) Second harmonic generation imaging of cancer. Methods Cell Biol 123:531–546

    Article  PubMed  Google Scholar 

  • Kim SY, Park C, Kim HJ, Park J, Hwang J, Kim JI, Choi MG, Kim S, Kim KM, Kang MS (2015) Deregulation of immune response genes in patients with Epstein-Barr virus-associated gastric cancer and outcomes. Gastroenterology 148:137–147

    Article  CAS  PubMed  Google Scholar 

  • Kim HS, Shin SJ, Beom SH, Jung M, Choi YY, Son T (2016) Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy. Oncotarget 7:44608–44620

    PubMed  PubMed Central  Google Scholar 

  • Klintrup K, Mäkinen JM, Kauppila S, Väre PO, Melkko J, Tuominen H, Tuppurainen K, Mäkelä J, Karttunen TJ, Mäkinen MJ (2005) Inflammation and prognosis in colorectal cancer. Eur J Cancer 41:2645–2654

    Article  PubMed  Google Scholar 

  • Lu J, Zhou S, Siech M, Seufferlein T, Bachem MG (2014) Pancreatic stellate cells promote hapto-migration of cancer cells through collagen I-mediated signalling pathway. Br J Cancer 110:409–420

    Article  CAS  PubMed  Google Scholar 

  • Moserle L, Casanovas O (2013) Anti-angiogenesis and metastasis: a tumour and stromal cell alliance. J Intern Med 273:128–137

    Article  CAS  PubMed  Google Scholar 

  • Mouw JK, Ou G, Weaver VM (2014) Extracellular matrix assembly: a multiscale deconstruction. Nat Rev Mol Cell Biol 15:771–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Müerköster S, Wegehenkel K, Arlt A, Witt M, Sipos B, Kruse ML, Sebens T, Klöppel G, Kalthoff H, Fölsch UR, Schäfer H (2004) Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1beta. Cancer Res 64:1331–1337

    Article  PubMed  Google Scholar 

  • Murphy G, Pfeiffer R, Camargo MC, Rabkin CS (2009) Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology 137:824–833

    Article  PubMed  PubMed Central  Google Scholar 

  • Navab R, Strumpf D, Bandarchi B, Zhu CQ, Pintilie M, Ramnarine VR, Ibrahimov E, Radulovich N, Leung L, Barczyk M, Panchal D, To C, Yun JJ, Der S, Shepherd FA, Jurisica I, Tsao MS (2011) Prognostic gene-expression signature of carcinoma-associated fibroblasts in non–small cell lung cancer. Proc Natl Acad Sci USA 108:7160–7165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park JH, Richards CH, McMillan DC, Horgan PG, Roxburgh CS (2014) The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann Oncol 25:644–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park JH, McMillan DC, Powell AG, Richards CH, Horgan PG, Edwards J (2015) Evaluation of a tumor microenvironment-based prognostic score in primary operable colorectal cancer. Clin Cancer Res 21:882–888

    Article  CAS  PubMed  Google Scholar 

  • Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ (2008) Collagen density promotes mammary tumor initiation and progression. BMC Med 6:11

    Article  PubMed  PubMed Central  Google Scholar 

  • Romano E, Romero P (2015) The therapeutic promise of disrupting the PD-1/PD-L1 immune checkpoint in cancer: unleashing the CD8 T cell mediated anti-tumor activity results in significant, unprecedented clinical efficacy in various solid tumors. J Immunother. Cancer 3:15

    Google Scholar 

  • Roxburgh CS, McMillan DC (2012) The role of the in situ local inflammatory response in predicting recurrence and survival in patients with primary operable colorectal cancer. Cancer Treat Rev. 2012:451–466

    Article  Google Scholar 

  • Shields MA, Dangi-Garimella S, Redig AJ, Munshi HG (2012) Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression. Biochem J 441:541–552

    Article  CAS  PubMed  Google Scholar 

  • Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pagès F, Galon J (2011) Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 71:1263–1271

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Ma W, Wang J, Yu L, Zhang X, Wang Z, Tan B, Wang N, Bai B, Yang S, Liu H, Zhu S, Cheng Y (2012) Tumor-stroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma. J Thorac Oncol 7:1457–1461

    Article  PubMed  Google Scholar 

  • Wang B, Wu S, Zeng H, Dong W, He W, Chen X, Dong X, Zheng L, Lin T, Huang J (2015) CD103(+)tumor infiltrating lymphocytes predict a favorable prognosis in urothelial cell carcinoma of the bladder. J Urol 194:556–562

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Basic Research Program of China (973 Program, No. 2010CB529400).

Author information

Authors and Affiliations

  1. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Gaotanyan 30, Chongqing, 400038, China

    Zhi-Hua Zhou, Cheng-Dong Ji, Jiang Zhu, You-Hong Cui & Xiu-Wu Bian

  2. Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China

    Zhi-Hua Zhou, Cheng-Dong Ji, You-Hong Cui & Xiu-Wu Bian

  3. Department of Pathology, The 101 Hospital of People’s Liberation Army, Wuxi, Jiangsu Province, China

    Zhi-Hua Zhou & Hai-Bin Zhao

  4. Department of Pathology, Daping Hospital, Third Military Medical University, Chongqing, China

    Hua-Liang Xiao

Authors
  1. Zhi-Hua Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cheng-Dong Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hua-Liang Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hai-Bin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. You-Hong Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiu-Wu Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiu-Wu Bian.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIF 865 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, ZH., Ji, CD., Zhu, J. et al. The prognostic value and pathobiological significance of Glasgow microenvironment score in gastric cancer. J Cancer Res Clin Oncol 143, 883–894 (2017). https://doi.org/10.1007/s00432-017-2346-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-017-2346-1

Keywords

Search

Navigation