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Periostin⁺ cancer-associated fibroblasts promote lymph node metastasis by impairing the lymphatic endothelial barriers in cervical squamous cell carcinoma.

ABSTRACT: Lymph node metastasis (LNM), a critical prognostic determinant in cancer patients, is critically influenced by the presence of numerous heterogeneous cancer-associated fibroblasts (CAFs) in the tumor microenvironment. However, the phenotypes and characteristics of the various pro-metastatic CAF subsets in cervical squamous cell carcinoma (CSCC) remain unknown. Here, we describe a CAF subpopulation with elevated periostin expression (periostin⁺ CAFs), located in the primary tumor sites and metastatic lymph nodes, that positively correlated with LNM and poor survival in CSCC patients. Mechanistically, periostin⁺ CAFs impaired lymphatic endothelial barriers by activating the integrin-FAK/Src-VE-cadherin signaling pathway in lymphatic endothelial cells and consequently enhanced metastatic dissemination. In contrast, inhibition of the FAK/Src signaling pathway alleviated periostin-induced lymphatic endothelial barrier dysfunction and its related effects. Notably, periostin^- CAFs were incapable of impairing endothelial barrier integrity, which may explain the occurrence of CAF-enriched cases without LNM. In conclusion, we identified a specific periostin⁺ CAF subset that promotes LNM in CSCC, mainly by impairing the lymphatic endothelial barriers, thus providing the basis for potential stromal fibroblast-targeted interventions that block CAF-dependent metastasis.

SUBMITTER: Wei WF

PROVIDER: S-EPMC7782076 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Periostin<sup>+</sup> cancer-associated fibroblasts promote lymph node metastasis by impairing the lymphatic endothelial barriers in cervical squamous cell carcinoma.

Wei Wen-Fei WF Chen Xiao-Jing XJ Liang Luo-Jiao LJ Yu Lan L Wu Xiang-Guang XG Zhou Chen-Fei CF Wang Zi-Ci ZC Fan Liang-Sheng LS Hu Zheng Z Liang Li L Wang Wei W

Molecular oncology 20201112 1

Lymph node metastasis (LNM), a critical prognostic determinant in cancer patients, is critically influenced by the presence of numerous heterogeneous cancer-associated fibroblasts (CAFs) in the tumor microenvironment. However, the phenotypes and characteristics of the various pro-metastatic CAF subsets in cervical squamous cell carcinoma (CSCC) remain unknown. Here, we describe a CAF subpopulation with elevated periostin expression (periostin<sup>+</sup> CAFs), located in the primary tumor sites ...[more]

PMID: 33124726

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Project description:Objective:To investigate the prevalence and distribution of cervical lymph node metastasis (LNM) in locally advanced supraglottic squamous cell carcinoma (LASCC) and guide the delineation of clinical lymph node target volumes. Materials and Methods:We reviewed patients defined as LASCC from January 2000 to December 2017 in our hospital. The primary tumor was operated on using partial or total laryngectomy, and all patients underwent bilateral neck dissection (levels II-IV at least). Univariate and multivariate logistic regressions were used to find risk factors associated with LNM. Results:A total of 206 patients were enrolled. In the whole group, the rate of ipsilateral metastasis (IM) was 60.9% (67 patients), whereas contralateral metastasis was 25.5% (28 patients). Only positive ipsilateral lymph nodes contributed to contralateral metastasis (p = 0.001). Seventy-six cases were diagnosed with clinical positive lymph nodes (cN+). IM of primary lesions mainly located within the unilateral sites (n = 49 patients) was detected in levels II, III, and IV with lymph node metastasis ratios of 73.5% (36 patients), 63.3% (31 patients), and 20.4% (10 patients), respectively, and contralateral metastasis of 36.7% (18 patients), 16.3% (8 patients), and 6.1% (3 patients), respectively. Involvement of level II or III was associated with metastasis of level IV. No one developed contralateral level IV involvement without metastasis of contralateral levels II and III. A total of 130 cases had clinically negative neck lymph nodes (cN0). The prevalence of occult metastasis (OM) was 35.4%. Among 62 patients with unilateral lesions, the rates of OM to ipsilateral neck levels II, III, and IV were 21, 11.1, and 1.6%, respectively, whereas contralateral neck levels were 6.3, 4.8, and 0%, respectively. In terms of the risk factors, histopathological differentiation was related to OM (p = 0.003). Two of 25 people were with level VIb metastasis, and both of them were with subglottic involvement. Conclusion:Neck levels II to IV are most frequently involved and should be included in clinical target volume (CTV) in cN+ patients. Contralateral IV may be omitted when contralateral levels II and III are negative. In cN0 patients, ipsilateral levels II and III are suggested to be included in the CTV, whereas whether contralateral levels II and III should be included needs further research.

Dataset Information

Periostin+ cancer-associated fibroblasts promote lymph node metastasis by impairing the lymphatic endothelial barriers in cervical squamous cell carcinoma.

Publications

Periostin<sup>+</sup> cancer-associated fibroblasts promote lymph node metastasis by impairing the lymphatic endothelial barriers in cervical squamous cell carcinoma.

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Periostin⁺ cancer-associated fibroblasts promote lymph node metastasis by impairing the lymphatic endothelial barriers in cervical squamous cell carcinoma.