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PI3K? activates integrin ?4?1 to establish a metastatic niche in lymph nodes.

ABSTRACT: Lymph nodes are initial sites of tumor metastasis, yet whether the lymph node microenvironment actively promotes tumor metastasis remains unknown. We show here that VEGF-C/PI3K?-driven remodeling of lymph nodes promotes tumor metastasis by activating integrin ?4?1 on lymph node lymphatic endothelium. Activated integrin ?4?1 promotes expansion of the lymphatic endothelium in lymph nodes and serves as an adhesive ligand that captures vascular cell adhesion molecule 1 (VCAM-1)(+) metastatic tumor cells, thereby promoting lymph node metastasis. Experimental induction of ?4?1 expression in lymph nodes is sufficient to promote tumor cell adhesion to lymphatic endothelium and lymph node metastasis in vivo, whereas genetic or pharmacological blockade of integrin ?4?1 or VCAM-1 inhibits it. As lymph node metastases accurately predict poor disease outcome, and integrin ?4?1 is a biomarker of lymphatic endothelium in tumor-draining lymph nodes from animals and patients, these results indicate that targeting integrin ?4?1 or VCAM to inhibit the interactions of tumor cells with the lymph node microenvironment may be an effective strategy to suppress tumor metastasis.

SUBMITTER: Garmy-Susini B

PROVIDER: S-EPMC3670313 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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PI3Kα activates integrin α4β1 to establish a metastatic niche in lymph nodes.

Garmy-Susini Barbara B Avraamides Christie J CJ Desgrosellier Jay S JS Schmid Michael C MC Foubert Philippe P Ellies Lesley G LG Lowy Andrew M AM Blair Sarah L SL Vandenberg Scott R SR Datnow Brian B Wang Huan-You HY Cheresh David A DA Varner Judith J

Proceedings of the National Academy of Sciences of the United States of America 20130513 22

Lymph nodes are initial sites of tumor metastasis, yet whether the lymph node microenvironment actively promotes tumor metastasis remains unknown. We show here that VEGF-C/PI3Kα-driven remodeling of lymph nodes promotes tumor metastasis by activating integrin α4β1 on lymph node lymphatic endothelium. Activated integrin α4β1 promotes expansion of the lymphatic endothelium in lymph nodes and serves as an adhesive ligand that captures vascular cell adhesion molecule 1 (VCAM-1)(+) metastatic tumor c ...[more]

PMID: 23671068

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Project description:Objectives18F-fluorodeoxyglucose (FDG) PET/CT has been widely used in tumor diagnosis, staging, and response evaluation. To determine an optimal therapeutic strategy for lung cancer patients, accurate staging is essential. Semi-quantitative standardized uptake value (SUV) is known to be affected by multiple factors and may fail to differentiate between benign and malignant lesions. Lymph nodes (LNs) in the mediastinal and pulmonary hilar regions with high FDG uptake due to granulomatous lesions such as tuberculosis, which has a high prevalence in China, pose a diagnostic challenge. This study aims to evaluate the diagnostic value of the quantitative metabolic parameters derived from dynamic 18F-FDG PET/CT in differentiating metastatic and non-metastatic LNs in lung cancer.MethodsOne hundred and eight patients with pulmonary nodules were enrolled to perform 18F-FDG PET/CT dynamic + static imaging with informed consent. One hundred and thirty-five LNs in 29 lung cancer patients were confirmed by pathology. Static image analysis parameters including LN-SUVmax, LN-SUVmax/primary tumor SUVmax (LN-SUVmax/PT-SUVmax), mediastinal blood pool SUVmax (MBP-SUVmax), LN-SUVmax/MBP-SUVmax, and LN-SUVmax/short diameter. Quantitative parameters including K1, k2, k3 and Ki and of each LN were obtained by applying the irreversible two-tissue compartment model using in-house Matlab software. Ki/K1 was computed subsequently as a separate marker. We further divided the LNs into mediastinal LNs (N=82) and pulmonary hilar LNs (N=53). Wilcoxon rank-sum test or Independent-samples T-test and receiver-operating characteristic (ROC) analysis was performed on each parameter to compare the diagnostic efficacy in differentiating lymph node metastases from inflammatory uptake. P<0.05 were considered statistically significant.ResultsAmong the 135 FDG-avid LNs confirmed by pathology, 49 LNs were non-metastatic, and 86 LNs were metastatic. LN-SUVmax, MBP-SUVmax, LN-SUVmax/MBP-SUVmax, and LN-SUVmax/short diameter couldn't well differentiate metastatic from non-metastatic LNs (P>0.05). However, LN-SUVmax/PT-SUVmax have good performance in the differential diagnosis of non-metastatic and metastatic LNs (P=0.039). Dynamic metabolic parameters in addition to k3, the parameters including K1, k2, Ki, and Ki/K1, on the other hand, have good performance in the differential diagnosis of metastatic and non-metastatic LNs (P=0.045, P=0.001, P=0.001, P=0.001, respectively). For ROC analysis, the metabolic parameters Ki (AUC of 0.672 [0.579-0.765], sensitivity 0.395, specificity 0.918) and Ki/K1 (AUC of 0.673 [0.580-0.767], sensitivity 0.570, specificity 0.776) have good performance in the differential diagnosis of metastatic from non-metastatic LNs than SUVmax (AUC of 0.596 [0.498-0.696], sensitivity 0.826, specificity 0.388), included the mediastinal region and pulmonary hilar region.ConclusionCompared with SUVmax, quantitative parameters such as K1, k2, Ki and Ki/K1 showed promising results for differentiation of metastatic and non-metastatic LNs with high uptake. The Ki and Ki/K1 had a high differential diagnostic value both in the mediastinal region and pulmonary hilar region.

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PI3K? activates integrin ?4?1 to establish a metastatic niche in lymph nodes.

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PI3Kα activates integrin α4β1 to establish a metastatic niche in lymph nodes.

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