duzce med j Duzce Medical Journal 1307-671X Duzce University 10.18678/dtfd.1805761 Pathology Cancer Cell Biology Cancer Diagnosis Patoloji Kanser Hücre Biyolojisi Kanser Tanısı COL6A6 Downregulation and Stromal Remodeling as Predictors of an Aggressive Tumor Microenvironment in Lung Adenocarcinoma https://orcid.org/0000-0001-7297-9869 Yaldir Emel Eskişehir Osmangazi University, Faculty of Medicine, Department of Pathology https://orcid.org/0000-0002-1091-6974 Aktaş Sedef Hande Eskişehir Osmangazi University, Department of Biotechnology and Biosafety https://orcid.org/0000-0002-9341-6579 Dündar Emine Eskişehir Osmangazi University, Faculty of Medicine, Department of Pathology 04 25 2026 28 1 47 51 10 17 2025 03 13 2026 Copyright © 1999, Duzce Medical Journal 1999 Duzce Medical Journal

Aim: Collagen type VI alpha 6 chain (COL6A6), a component of the extracellular matrix, has been implicated in the regulation of tumor growth and metastasis. This study aimed to investigate the relationship between stromal COL6A6 expression, desmoplasia, lymph node metastasis, and PD-L1 expression in lung adenocarcinoma. Material and Methods: Sixty-two cases with lung adenocarcinoma were retrospectively analyzed. Desmoplasia was categorized as mild/absent or marked based on histopathological evaluation. Immunohistochemical staining for COL6A6 was performed, and tumors were classified as negative or positive according to stromal staining patterns. PD-L1 (DAKO 22C3) expression was evaluated in available cases using the tumor proportion score. Results: Loss of stromal COL6A6 expression was observed in 66.1% (n=41) of tumors, whereas all adjacent normal lung tissues showed strong expression. A statistically significant inverse association was identified between COL6A6 expression and desmoplasia (p<0.001). Tumors with marked desmoplasia showed a higher frequency of lymph nodes. Similarly, lymph node metastasis was more frequent in COL6A6-negative tumors, although this difference did not reach statistical significance. PD-L1 positivity was more frequently observed in tumors with marked desmoplasia and in those lacking COL6A6 expression. Conclusion: COL6A6 expression is markedly downregulated in lung adenocarcinoma and shows an inverse association with desmoplasia. Loss of COL6A6 may reflect an aggressive tumor microenvironment and could be associated with increased PD-L1 expression. These findings suggest that COL6A6 may serve as a potential prognostic and predictive biomarker in lung adenocarcinoma, warranting further investigation in larger cohorts.

 COL6A6 protein lung adenocarcinoma fibrosis lymph node metastasis PD-L1 Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. doi:10.3322/caac.21660. Iglesia MD, Parker JS, Hoadley KA, Serody JS, Perou CM, Vincent BG. Genomic analysis of immune cell infiltrates across 11 tumor types. J Natl Cancer Inst. 2016;108(11):djw144. doi:10.1093/jnci/djw144. Long R, Liu Z, Li J, Yu H. COL6A6 interacted with P4HA3 to suppress the growth and metastasis of pituitary adenoma via blocking PI3K-Akt pathway. Aging (Albany NY). 2019;11(20):8845-59. doi:10.18632/aging.102300. Qiao H, Feng Y, Tang H. COL6A6 inhibits the proliferation and metastasis of non-small cell lung cancer through the JAK signalling pathway. Transl Cancer Res. 2021;10(10):4514-22. doi:10.21037/tcr-21-2002. Ni YB, Tsang JY, Chan SK, Tse GM. A novel morphologic-molecular recurrence predictive model refines traditional prognostic tools for invasive breast carcinoma. Ann Surg Oncol. 2014;21(9):2928-33. doi:10.1245/s10434-014-3691-9. Mujtaba SS, Ni YB, Tsang JY, Chan SK, Yamaguchi R, Tanaka M, et al. Fibrotic focus in breast carcinomas: relationship with prognostic parameters and biomarkers. Ann Surg Oncol. 2013;20(9):2842-9. doi:10.1245/s10434-013-2955-0. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi:10.3322/caac.21551. Naba A, Pearce OMT, Del Rosario A, Ma D, Ding H, Rajeeve V, et al. Characterization of the extracellular matrix of normal and diseased tissues using proteomics. J Proteome Res. 2017;16(8):3083-91. doi:10.1021/acs.jproteome.7b00191. Castagnaro S, Gambarotto L, Cescon M, Bonaldo P. Autophagy in the mesh of collagen VI. Matrix Biol. 2021;100-101:162-72. doi:10.1016/j.matbio.2020.12.004. Sirisena ND, Samaranayake UMJE, Neto OLA, Foley AR, Patrihana BAPS, Neththikumara N, et al. A novel variant in the COL6A1 gene causing Ullrich congenital muscular dystrophy in a consanguineous family: a case report. BMC Neurol. 2021;21(1):105. doi:10.1186/s12883-021-02134-7. Li JD, Deng LL, Luo JY, Mo CH, Chi BT, Huang WY, et al. The role of collagen type VI alpha 6 chain as a potential tumor suppressor in breast cancer: an immune regulation perspective. BMC Cancer. 2025;25(1):1363. doi:10.1186/s12885-025-14680-1. Gambichler T, Elfering J, Meyer T, Bruckmüller S, Stockfleth E, Skrygan M, et al. Protein expression of prognostic genes in primary melanoma and benign nevi. J Cancer Res Clin Oncol. 2022;148(10):2673-80. doi:10.1007/s00432-021-03779-0. Liang L, Li J, Yu J, Liu J, Xiu L, Zeng J, et al. Establishment and validation of a novel invasion-related gene signature for predicting the prognosis of ovarian cancer. Cancer Cell Int. 2022;22(1):118. doi:10.1186/s12935-022-02502-4. Ma Y, Qiu M, Guo H, Chen H, Li J, Li X, et al. Comprehensive analysis of the immune and prognostic implication of COL6A6 in lung adenocarcinoma. Front Oncol. 2021;11:633420. doi:10.3389/fonc.2021.633420. Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol. 2013;31(1):675-704. doi:10.1146/annurev-immunol-032712-095946. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff M, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6(2):202-16. doi:10.1158/2159-8290.CD-15-0283. Lastwika KJ, Wilson W 3rd, Li QK, Norris J, Xu H, Ghazarian SR, et al. Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res. 2016;76(2):227-38. doi:10.1158/0008-5472.CAN-14-3362. Zhao F, Evans K, Xiao C, DeVito N, Theivanthiran B, Holtzhausen A, et al. Stromal fibroblasts mediate anti-PD-1 resistance via MMP-9 and dictate TGFβ inhibitor sequencing in melanoma. Cancer Immunol Res. 2018;6(12):1459-71. doi:10.1158/2326-6066.CIR-18-0086.