Distribution and Clinicopathological Characteristics of G-CSF Expression in Tumor Cells and Stromal Cells in Upper Tract Urothelial Carcinoma

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2024 Dec 31

PMID 39739128

Authors

Go Kobayashi

Yohei Sekino

Hikaru Nakahara

Kohei Kobatake

Keisuke Goto

Tetsutaro Hayashi

Kazuhiro Sentani

Nobuyuki Hinata

Affiliations

Soon will be listed here.

Abstract

Background: Urothelial carcinoma (UC) is a common type of malignant disease; however, the diagnostic and prognostic markers of upper urinary tract urothelial cancer (UTUC) remain poorly understood because of its rarity.

Methods: To clarify the clinicopathological significance of granulocyte-colony stimulating factor (G-CSF) in UTUC, we analyzed the expression and distribution of G-CSF in 112 upper tract urothelial carcinoma (UTUC) samples with immunohistochemistry.

Results: In normal urothelium, G-CSF expression was weak or absent, whereas high expression of G-CSF was observed in UTUC tissues, both in tumor cells (TCs) and stromal cells (SCs). G-CSF expression in the TCs and SCs was associated with nodular/flat morphology, high grade, advanced T stage, and lymphovascular invasion in UTUC. G-CSF expression in SCs was associated with poor prognosis and was an independent prognostic factor. Public data showed that G-CSF expression was also associated with decreased progression-free survival and disease-specific survival. A prognostic model was constructed by incorporating the presence or absence of G-CSF expression along with clinicopathologic factors, which allowed for a more accurate prediction of poor prognosis. We further showed that G-CSF expression was associated with a high Ki-67 labeling index and with PD-L1, HER2, and p53 expression in UTUC.

Conclusion: G-CSF expression in TCs and SCs may play a crucial role in UTUC tumor progression. Notably, stromal G-CSF expression showed significant prognostic value, even when compared to major clinicopathological factors, suggesting that the evaluation of G-CSF expression may contribute to clinical decision-making in patients with UTUC.

References

Abouassaly R, Alibhai S, Shah N, Timilshina N, Fleshner N, Finelli A . Troubling outcomes from population-level analysis of surgery for upper tract urothelial carcinoma. Urology. 2010; 76(4):895-901. DOI: 10.1016/j.urology.2010.04.020. View

Agarwal S, Lakoma A, Chen Z, Hicks J, Metelitsa L, Kim E . G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation. Cancer Res. 2015; 75(12):2566-79. PMC: 4470771. DOI: 10.1158/0008-5472.CAN-14-2946. View

Cetean S, Cainap C, Constantin A, Cainap S, Gherman A, Oprean L . The importance of the granulocyte-colony stimulating factor in oncology. Clujul Med. 2016; 88(4):468-72. PMC: 4689238. DOI: 10.15386/cjmed-531. View

Chan L, Li C, Xia W, Hsu J, Lee H, Cha J . IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest. 2019; 129(8):3324-3338. PMC: 6668668. DOI: 10.1172/JCI126022. View

Chen C, Tsai M, Chiang P, Sung M, Luo H, Suen J . Prognostic value of PD-L1 combined positive score in patients with upper tract urothelial carcinoma. Cancer Immunol Immunother. 2021; 70(10):2981-2990. PMC: 10992487. DOI: 10.1007/s00262-021-02890-y. View

Chen J, Zhong W, Yang M, Hou W, Wang X, Xia K . Development and validation of a PD-L1/PD-1/CD8 axis-based classifier to predict cancer survival of upper tract urothelial carcinoma after radical nephroureterectomy. Cancer Immunol Immunother. 2021; 70(9):2657-2668. PMC: 10992229. DOI: 10.1007/s00262-020-02827-x. View

Doheny D, Sirkisoon S, Carpenter R, Aguayo N, Regua A, Anguelov M . Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis. Oncogene. 2020; 39(42):6589-6605. PMC: 7572897. DOI: 10.1038/s41388-020-01454-1. View

Dwivedi P, Greis K . Granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies. Exp Hematol. 2016; 46:9-20. PMC: 5241233. DOI: 10.1016/j.exphem.2016.10.008. View

Fan Z, Li Y, Zhao Q, Fan L, Tan B, Zuo J . Highly Expressed Granulocyte Colony-Stimulating Factor (G-CSF) and Granulocyte Colony-Stimulating Factor Receptor (G-CSFR) in Human Gastric Cancer Leads to Poor Survival. Med Sci Monit. 2018; 24:1701-1711. PMC: 5880331. DOI: 10.12659/msm.909128. View

10.

Favaretto R, Zequi S, Oliveira R, Santana T, Costa W, Cunha I . Tissue-based molecular markers in upper tract urothelial carcinoma and their prognostic implications. Int Braz J Urol. 2017; 44(1):22-37. PMC: 5815529. DOI: 10.1590/S1677-5538.IBJU.2017.0204. View

11.

Fujii Y, Sato Y, Suzuki H, Kakiuchi N, Yoshizato T, Lenis A . Molecular classification and diagnostics of upper urinary tract urothelial carcinoma. Cancer Cell. 2021; 39(6):793-809.e8. PMC: 9110171. DOI: 10.1016/j.ccell.2021.05.008. View

12.

Furmento V, Marino J, Blank V, Roguin L . The granulocyte colony-stimulating factor (G-CSF) upregulates metalloproteinase-2 and VEGF through PI3K/Akt and Erk1/2 activation in human trophoblast Swan 71 cells. Placenta. 2014; 35(11):937-46. DOI: 10.1016/j.placenta.2014.09.003. View

13.

Han Y, Liu D, Li L . PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020; 10(3):727-742. PMC: 7136921. View

14.

He K, Liu X, Hoffman R, Shi R, Lv G, Gao J . G-CSF/GM-CSF-induced hematopoietic dysregulation in the progression of solid tumors. FEBS Open Bio. 2022; 12(7):1268-1285. PMC: 9249339. DOI: 10.1002/2211-5463.13445. View

15.

Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B . Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019; 18(1):10. PMC: 6332843. DOI: 10.1186/s12943-018-0928-4. View

16.

Jones S, Jenkins B . Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018; 18(12):773-789. DOI: 10.1038/s41577-018-0066-7. View

17.

Karagiannidis I, Salataj E, Egal E, Beswick E . G-CSF in tumors: Aggressiveness, tumor microenvironment and immune cell regulation. Cytokine. 2021; 142:155479. PMC: 8044051. DOI: 10.1016/j.cyto.2021.155479. View

18.

Karanovic S, Ardin M, Tang Z, Tomic K, Villar S, Renard C . Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure. Int J Cancer. 2021; 150(2):374-386. PMC: 8627473. DOI: 10.1002/ijc.33827. View

18.

Hagiwara M, Kikuchi E, Kosaka T, Mikami S, Saya H, Oya M . Variant isoforms of CD44 expression in upper tract urothelial cancer as a predictive marker for recurrence and mortality. Urol Oncol. 2016; 34(8):337.e19-26. DOI: 10.1016/j.urolonc.2016.03.015. View

19.

Kobayashi G, Hayashi T, Sentani K, Babasaki T, Sekino Y, Inoue S . Clinicopathological significance of claspin overexpression and its efficacy as a novel biomarker for the diagnosis of urothelial carcinoma. Virchows Arch. 2021; 480(3):621-633. DOI: 10.1007/s00428-021-03239-7. View