Qun Zhang1,2, Duojie Li1,2,3, Chaomang Zhu1, Jie Huang1, Shixiang Zhou1,*
1Department of Radiotherapy, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233030, Anhui, China.
2Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu 233000, Anhui, China.
3Joint Research Center for Regional Diseases of IHM, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233030, Anhui, China.
*Corresponding author: Shixiang Zhou
This work was supported by the Anhui Province Key Laboratory Open Projects (Bengbu Medical College, No. KFDX202204), the 2025 Provincial Health and Wellness Science and Technology Project (No. 2025BAn30013), and the University Research Projects of the Anhui Provincial Department of Education (No. 2025AHGXZK40692).
Abstract
Background: Esophageal squamous cell carcinoma (ESCC) remains a major cause of cancer mortality, and postoperative risk assessment is still anchored mainly in pathological stage and lymph node status. Fibroblast-specific protein-1 (FSP1), also known as S100A4, has been linked to cell motility, epithelial-mesenchymal transition, and tumor-stromal remodeling. Its relationship with nodal metastatic burden in resected ESCC, however, has not been fully clarified. Methods: We retrospectively analyzed 121 patients with surgically resected ESCC and 20 adjacent non-tumor tissue samples. FSP1/S100A4 expression was assessed by immunohistochemistry and classified as low (-/+) or high (2+/3+). Associations with clinicopathological variables, lymph node metastasis, positive lymph node count, lymph node ratio (LNR), Ki-67 index, and overall survival (OS) were evaluated. Kaplan-Meier analysis, log-rank testing, and Cox regression were performed for OS. Results: FSP1/S100A4 positivity was present in 110 of 121 ESCC samples (90.9%) and in none of the 20 adjacent non-tumor samples (P<0.0001). High FSP1/S100A4 expression was identified in 53 patients (43.8%) and was associated with lymph node-positive disease (P=0.0014), higher N category (P=0.0032), higher pathological stage group (P=0.0042), more positive lymph nodes (median 2 vs. 0; P=0.0002), higher LNR (median 0.14 vs. 0.00; P=0.0011), and a slightly higher Ki-67 distribution (P=0.0251). Ordered FSP1/S100A4 expression correlated positively with N category, positive lymph node count, LNR, and Ki-67, and inversely with OS. Patients with high FSP1/S100A4 expression had shorter OS than those with low expression (median OS, 18 vs. 37 months; log-rank P=0.0071). In univariate Cox analysis, high FSP1/S100A4 expression was associated with worse OS (HR=1.86, 95% CI 1.17-2.95, P=0.0089), but the association was attenuated after adjustment for N category or LNR. Conclusions: In this cohort of resected ESCC, FSP1/S100A4 was frequently expressed in tumor tissue and was closely related to nodal metastatic burden and poorer postoperative survival. Its prognostic effect was not independent of nodal variables, suggesting that FSP1/S100A4 is best interpreted as a potential adjunctive pathological marker of nodal metastatic aggressiveness rather than as a stand-alone survival determinant.
References
[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-63.
[2] Qi L, Cao F, Zhao G, et al. Global esophageal cancer epidemiology in 2022 and predictions for 2050: a comprehensive analysis and projections based on GLOBOCAN data. Chin Med J (Engl). 2024;137:2750-60.
[3] Liu CQ, Ma YL, Qin Q, et al. Epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040. Thorac Cancer. 2023;14:3-11.
[4] van Hagen P, Hulshof MCCM, van Lanschot JJB, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074-84.
[5] Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759-71.
[6] Rice TW, Ishwaran H, Ferguson MK, et al. Cancer of the esophagus and esophagogastric junction: an eighth edition staging primer. J Thorac Oncol. 2017;12:36-42.
[7] Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-9.
[8] Wilson M, Rosato EL, Chojnacki KA, et al. Prognostic significance of lymph node metastases and ratio in esophageal can-cer. J Surg Res. 2008;146:11-5.
[9] Chen P, Liu Z, Zhang Y, et al. Lymph node ratio is a prognostic indicator for locally advanced esophageal squamous cell carcinoma after neoadjuvant immunotherapy plus chemotherapy. Front Oncol. 2024;13:1324895.
[10] Qureshi S, Alghamdi A, Zubair M, et al. Prognostic significance of lymph node ratio in esophageal squamous cell carcinoma patients undergoing concurrent neoadjuvant therapy followed by minimally invasive esophagectomy. World J Surg Oncol. 2025;23:32.
[11] Booka E, Takeuchi H, Kikuchi H, et al. Impact of dissected lymph node count and positive lymph node ratio after esophagectomy: a systematic review and meta-analysis. Ann Surg Open. 2025;6:e546.
[12] Helfman DM, Kim EJ, Lukanidin E, et al. The metastasis associated protein S100A4: role in tumour progression and metastasis. Br J Cancer. 2005;92:1955-8.
[13] Fei F, Qu J, Li C, et al. Role of metastasis-induced protein S100A4 in human non-tumor pathophysiologies. Cell Biosci. 2017 Nov 25;7:64.
[14] Bogachek M, Kazakova M, Matveeva O, et al. S100A4/FSP1: a prognostic marker and a promising target for antitumor therapy. Int J Mol Sci. 2025;26:9370.
[15] Wong T, Yang Z, Liew PX, et al. The multi-faceted immune modulatory role of S100A4 in cancer and chronic inflammatory disease. Front Immunol. 2025;16:1525567.
[16] Ninomiya I, Ohta T, Fushida S, et al. Increased expression of S100A4 and its prognostic significance in esophageal squamous cell carcinoma. Int J Oncol. 2001;18:715-20.
[17] Chen D, Zheng XF, Yang ZM, et al. S100A4 silencing blocks invasive ability of esophageal squamous cell carcinoma cells. World J Gastroenterol. 2012;18:915-22.
[18] Chai J, Jamal MM. S100A4 in esophageal cancer: is this the one to blame? World J Gastroenterol. 2012;18:3931-5.
[19] Dunbar KJ, Muir AB. Cancer-associated fibroblasts in esophageal cancer. Cancers (Basel). 2024;16:1038.
[20] Qiu L, Wang Y, Liu M, et al. Cancer-associated fibroblasts: an emerging target against esophageal squamous cell carcinoma. Cancer Lett. 2022;533:215599.
[21] Ren Q, Zhang P, Lin H, et al. A fibroblast-associated signature predicts prognosis and immunotherapy response in esophageal squamous cell carcinoma. Front Immunol. 2023;14:1182162.
[22] Qiu L, Yue J, Ding L, et al. Cancer-associated fibroblasts: an emerging target against esophageal squamous cell carcinoma. Cancer Lett. 2022;546:215860.
[23] Jiang J, Xu C, Han D, et al. Functional heterogeneity of cancer-associated fibroblasts with distinct neoadjuvant immunotherapy plus chemotherapy response in esophageal squamous cell carcinoma. Biomark Res. 2024;12:113.
[24] Ha SY, Yeo SY, Xuan YH, et al. The prognostic significance of cancer-associated fibroblasts in esophageal squamous cell carcinoma. PLoS One. 2014;9:e99955.
[25] Uxa S, Castillo-Binder P, Kohler R, et al. Ki-67 gene expression. Cell Death Differ. 2021;28:3357-70.