The effect of Wnt5a derived from tumor associated fibroblasts on the invasion and migration of gastric cancer cells and its correlation with clinicopathological features of gastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

CHEN Tao ¹ , YANG Tao ¹ , LIU Lixin ¹ , LIU Kang ² ,  XIA Shusen ¹

1. Gastroenterology Department 2, Affiliated Hospital of North Sichuan Medical College and Hepatobiliary, Pancreatic and Intestinal Institute, Nanchong, Sichuan 637000, P. R. China;
2. Beijing Anzhen Hospital Affiliated to Capital Medical University Nanchong Hospital·Nanchong Central Hospital/Organization Engineering and Stem Cell Research Institute of the Second Clinical School of North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;

Corresponding author：

XIA Shusen, Email: xsx0639@163.com

Keywords：

gastric cancer; Wnt5a; cancer-ssociated fibroblasts; tumor microenvironment; migration; invasion

DOI：

10.7507/1007-9424.202401075

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the effect of Wnt5a derived from tumor-associated fibroblasts （CAFs） on the migration and invasion of gastric cancer cells. Methods The differentially expressed genes Wnt5a between CAFs and normal gastric fibroblasts (NGFs) in gastric cancer tissues and their corresponding normal gastric tissues using the GEO database GSE194261 dataset were screened. Immunohistochemical method was used to detect the expression of Wnt5a protein in tissue samples of clinical gastric cancer patients, and the relationship between Wnt5a protein expression and clinicopathological features of gastric cancer was analyzed. CAFs and NGFs were extracted from fresh surgical specimens of gastric cancer patients, and the expression of Wnt5a in CAFs was detected by real-time fluorescence quantitative-polymerase chain reaction and Western blot experiment. Transwell invasion and migration experiment was used to observe the effects of CAFs, inhibition of Wnt5a expression in CAFs and different concentrations of recombinant Wnt5a protein on the migration and invasion ability of gastric cancer MGC-803 and MKN-28 cell lines in vitro. Results Through the screening of GEO database GSE194261 data set, it was found that Wnt5a was more expressed in CAFs than NGFs (P<0.05). Immunohistochemical results showed that the expression of Wnt5a protein in gastric cancer tissues was significantly stronger than that in normal gastric tissues (P<0.05), and the expression of Wnt5a protein was related to T stage of tumor (χ²=5.035, P<0.05), but not related to gender, age, degree of tumor differentiation, lymph node metastasis, vascular invasion and nerve invasion (P>0.05). Inhibiting Wnt5a derived from CAFs could inhibit the invasion and migration of gastric cancer cells. By stimulating gastric cancer cells with different concentrations of human recombinant Wnt5a protein, it was found that when the concentration of human recombinant Wnt5a protein was greater than 100 ng/mL, the invasion and migration abilities of MGC-803 and MKN-28 gastric cancer cells were significantly increased (P<0.05). Conclusion Wnt5a is highly expressed in CAFs derived from the interstitial tissue of gastric cancer, which is related to the invasion depth of gastric cancer and can promote the invasion and migration of gastric cancer cells.

Citation： CHEN Tao, YANG Tao, LIU Lixin, LIU Kang, XIA Shusen. The effect of Wnt5a derived from tumor associated fibroblasts on the invasion and migration of gastric cancer cells and its correlation with clinicopathological features of gastric cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2024, 31(7): 848-857. doi: 10.7507/1007-9424.202401075 Copy

1.	Machlowska J, Baj J, Sitarz M, et al. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci, 2020, 21(11): 4012. doi: 10.3390/ijms21114012.
2.	Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl), 2021, 134(7): 783-791.
3.	Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33.
4.	Arneth B. Tumor microenvironment. Medicina (Kaunas), 2019, 56(1): 15. doi: 10.3390/medicina56010015.
5.	Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature, 2004, 432(7015): 332-337.
6.	Aizawa T, Karasawa H, Funayama R, et al. Cancer-associated fibroblasts secrete Wnt2 to promote cancer progression in colorectal cancer. Cancer Med, 2019, 8(14): 6370-6382.
7.	Hu YB, Yan C, Mu L, et al. Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance. Oncogene, 2019, 38(11): 1951-1965.
8.	Kennerdell JR, Fetter RD, Bargmann CI. Wnt-Ror signaling to SIA and SIB neurons directs anterior axon guidance and nerve ring placement in C. elegans. Development, 2009, 136(22): 3801-3810.
9.	Bittner M, Meltzer P, Chen Y, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature, 2000, 406(6795): 536-540.
10.	Rojas A, Araya P, Gonzalez I, et al. Gastric tumor microen-vironment. Adv Exp Med Biol, 2020, 1226: 23-35.
11.	Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, 2011, 144(5): 646-674.
12.	Giusti I, Di Francesco M, Poppa G, et al. Tumor-derived extracellular vesicles activate normal human fibroblasts to a cancer-associated fibroblast-like phenotype, sustaining a pro-tumorigenic microenvironment. Front Oncol, 2022, 12: 839880. doi: 10.3389/fonc.2022.839880.
13.	Shelton M, Anene CA, Nsengimana J, et al. The role of CAF derived exosomal microRNAs in the tumour microenvironment of melanoma. Biochim Biophys Acta Rev Cancer, 2021, 1875(1): 188456. doi: 10.1016/j.bbcan.2020.188456.
14.	Wu X, Tao P, Zhou Q, et al. IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget, 2017, 8(13): 20741-20750.
15.	Shi L, Wang Z, Geng X, et al. Exosomal miRNA-34 from cancer-associated fibroblasts inhibits growth and invasion of gastric cancercells in vitro and in vivo. Aging (Albany NY), 2020, 12(9): 8549-8564.
16.	Kramer N, Schmöllerl J, Unger C, et al. Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene, 2017, 36(39): 5460-5472.
17.	Hirashima T, Karasawa H, Aizawa T, et al. Wnt5a in cancer-associated fibroblasts promotes colorectal cancer progression. Biochem Biophys Res Commun, 2021, 568: 37-42.
18.	Willert K, Brown JD, Danenberg E, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature, 2003, 423(6938): 448-452.
19.	Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol, 2020, 13(1): 165. doi: 10.1186/s13045-020-00990-3.
20.	凌煜玮, 康骅. 肿瘤相关成纤维细胞在肿瘤微环境中免疫调节作用的研究现状. 中国普外基础与临床杂志, 2020, 27(12): 1593-1597.
21.	Bueno MLP, Saad STO, Roversi FM. WNT5A in tumor development and progression: A comprehensive review. Biomed Pharmacother, 2022, 155: 113599. doi: 10.1016/j.biopha.2022.113599.
22.	Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 1982, 31(1): 99-109.
23.	Astudillo P. Wnt5a signaling in gastric cancer. Front Cell Dev Biol, 2020, 8: 110. doi: 10.3389/fcell.2020.00110.
24.	Ma Z, Li X, Mao Y, et al. Interferon-dependent SLC14A1⁺ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer. Cancer Cell, 2022, 40(12): 1550-1565.
25.	Li M, Zheng Y, Li X, et al. ATBF1 is a potential diagnostic marker of histological grade and functions via WNT5A in breast cancer. BMC Cancer, 2022, 22(1): 1280. doi: 10.1186/s12885-022-10380-2.
26.	Zhou W, Mei J, Gu D, et al. Wnt5a: A promising therapeutic target in ovarian cancer. Pathol Res Pract, 2021, 219: 153348. doi: 10.1016/j.prp.2021.153348.
27.	Dykes SS, Hughes VS, Wiggins JM, et al. Stromal cells in breast cancer as a potential therapeutic target. Oncotarget, 2018, 9(34): 23761-23779.

1. Machlowska J, Baj J, Sitarz M, et al. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci, 2020, 21(11): 4012. doi: 10.3390/ijms21114012.
2. Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl), 2021, 134(7): 783-791.
3. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33.
4. Arneth B. Tumor microenvironment. Medicina (Kaunas), 2019, 56(1): 15. doi: 10.3390/medicina56010015.
5. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature, 2004, 432(7015): 332-337.
6. Aizawa T, Karasawa H, Funayama R, et al. Cancer-associated fibroblasts secrete Wnt2 to promote cancer progression in colorectal cancer. Cancer Med, 2019, 8(14): 6370-6382.
7. Hu YB, Yan C, Mu L, et al. Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance. Oncogene, 2019, 38(11): 1951-1965.
8. Kennerdell JR, Fetter RD, Bargmann CI. Wnt-Ror signaling to SIA and SIB neurons directs anterior axon guidance and nerve ring placement in C. elegans. Development, 2009, 136(22): 3801-3810.
9. Bittner M, Meltzer P, Chen Y, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature, 2000, 406(6795): 536-540.
10. Rojas A, Araya P, Gonzalez I, et al. Gastric tumor microen-vironment. Adv Exp Med Biol, 2020, 1226: 23-35.
11. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, 2011, 144(5): 646-674.
12. Giusti I, Di Francesco M, Poppa G, et al. Tumor-derived extracellular vesicles activate normal human fibroblasts to a cancer-associated fibroblast-like phenotype, sustaining a pro-tumorigenic microenvironment. Front Oncol, 2022, 12: 839880. doi: 10.3389/fonc.2022.839880.
13. Shelton M, Anene CA, Nsengimana J, et al. The role of CAF derived exosomal microRNAs in the tumour microenvironment of melanoma. Biochim Biophys Acta Rev Cancer, 2021, 1875(1): 188456. doi: 10.1016/j.bbcan.2020.188456.
14. Wu X, Tao P, Zhou Q, et al. IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget, 2017, 8(13): 20741-20750.
15. Shi L, Wang Z, Geng X, et al. Exosomal miRNA-34 from cancer-associated fibroblasts inhibits growth and invasion of gastric cancercells in vitro and in vivo. Aging (Albany NY), 2020, 12(9): 8549-8564.
16. Kramer N, Schmöllerl J, Unger C, et al. Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene, 2017, 36(39): 5460-5472.
17. Hirashima T, Karasawa H, Aizawa T, et al. Wnt5a in cancer-associated fibroblasts promotes colorectal cancer progression. Biochem Biophys Res Commun, 2021, 568: 37-42.
18. Willert K, Brown JD, Danenberg E, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature, 2003, 423(6938): 448-452.
19. Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol, 2020, 13(1): 165. doi: 10.1186/s13045-020-00990-3.
20. 凌煜玮, 康骅. 肿瘤相关成纤维细胞在肿瘤微环境中免疫调节作用的研究现状. 中国普外基础与临床杂志, 2020, 27(12): 1593-1597.
21. Bueno MLP, Saad STO, Roversi FM. WNT5A in tumor development and progression: A comprehensive review. Biomed Pharmacother, 2022, 155: 113599. doi: 10.1016/j.biopha.2022.113599.
22. Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 1982, 31(1): 99-109.
23. Astudillo P. Wnt5a signaling in gastric cancer. Front Cell Dev Biol, 2020, 8: 110. doi: 10.3389/fcell.2020.00110.
24. Ma Z, Li X, Mao Y, et al. Interferon-dependent SLC14A1⁺ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer. Cancer Cell, 2022, 40(12): 1550-1565.
25. Li M, Zheng Y, Li X, et al. ATBF1 is a potential diagnostic marker of histological grade and functions via WNT5A in breast cancer. BMC Cancer, 2022, 22(1): 1280. doi: 10.1186/s12885-022-10380-2.
26. Zhou W, Mei J, Gu D, et al. Wnt5a: A promising therapeutic target in ovarian cancer. Pathol Res Pract, 2021, 219: 153348. doi: 10.1016/j.prp.2021.153348.
27. Dykes SS, Hughes VS, Wiggins JM, et al. Stromal cells in breast cancer as a potential therapeutic target. Oncotarget, 2018, 9(34): 23761-23779.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

The effect of Wnt5a derived from tumor associated fibroblasts on the invasion and migration of gastric cancer cells and its correlation with clinicopathological features of gastric cancer

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content