ABSTRACT
Organotropism during cancer metastasis occurs frequently but the underlying mechanism remains poorly understood. Here, we show that lysosomal protein transmembrane 5 (LAPTM5) promotes lung-specific metastasis in renal cancer. LAPTM5 sustains self-renewal and cancer stem cell-like traits of renal cancer cells by blocking the function of lung-derived bone morphogenetic proteins (BMPs). Mechanistic investigations showed that LAPTM5 recruits WWP2, which binds to the BMP receptor BMPR1A and mediates its lysosomal sorting, ubiquitination and ultimate degradation. BMPR1A expression was restored by the lysosomal inhibitor chloroquine. LAPTM5 expression could also serve as an independent predictor of lung metastasis in renal cancer. Lastly, elevation of LAPTM5 expression in lung metastases is a common phenomenon in multiple cancer types. Our results reveal a molecular mechanism underlying lung-specific metastasis and identify LAPTM5 as a potential therapeutic target for cancers with lung metastasis.
Subject(s)
Bone Morphogenetic Protein Receptors, Type I , Kidney Neoplasms , Lung Neoplasms , Ubiquitin-Protein Ligases , Bone Morphogenetic Protein Receptors, Type I/genetics , Bone Morphogenetic Protein Receptors, Type I/metabolism , Humans , Kidney Neoplasms/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lysosomes/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Ubiquitin-Protein Ligases/metabolismABSTRACT
BACKGROUND: Response prediction is necessary for renal cell carcinoma (RCC) tumors. We aim to evaluate parameters derived from 68 Ga-PSMA-11 PET/CT images for prediction of pathological VEGFR-2/PDGFR-ß expression of primary RCC tumors. METHODS: Forty-eight RCC patients were retrospectively enrolled with preoperative 68 Ga-PSMA-11 PET/CT scan and surgical specimen. Radiological parameters including tumor diameter, mean CT value, and maximal standard uptake value (SUVmax) were derived from PET/CT images and pathological VEGFR-2/PDGFR-ß/PSMA expression were identified with immunohistochemistry. Mann-Whitney U test was performed for continuous variables and the chi-square test for categorical variables. ROC was used for determining the effectiveness of preoperative parameters in differentiating VEGFR-2/PDGFR-ß expression. Univariate and multivariate logistic regression analyses were performed for significant parameters to predict VEGFR-2 & PDGFR-ß co-expression. RESULTS: Of the 48 tumors, 25 (52.1%) harbored positive VEGFR-2 expression, 28 (58.3%) harbored positive PDGFR-ß expression, and 24 (50%) were both VEGFR-2 positive and PDGFR-ß positive. SUVmax significantly differed by subgroups of VEGFR-2/PDGFR-ß expression (both P < 0.001). SUVmax demonstrated superior performance for differentiating VEGFR-2 & PDGFR-ß co-expression (positive vs. negative), with area under the curve 0.87 (95% CI 0.78-0.96, P < 0.001), sensitivity 93% and specificity 78%. Moreover, SUVmax was identified as the significant predictor for VEGFR-2 & PDGFR-ß co-expression (odds ratio 4.01, 95% CI 1.99-8.08, P < 0.001). Concordant with radiological findings with 68 Ga-PSMA-11 PET/CT, pathological PSMA staining intensity was significantly higher in both VEGFR-2-positive tumor and PDGFR-ß-positive tumor (P = 0.009 and P < 0.001, respectively). CONCLUSION: 68 Ga-PSMA-11 PET/CT could effectively identify pathological VEGFR-2/PDGFR-ß expression of primary RCC tumors, which may help with selection of mRCC patients suitable for TKIs treatment.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Positron Emission Tomography Computed Tomography/methods , Carcinoma, Renal Cell/diagnostic imaging , Vascular Endothelial Growth Factor Receptor-2 , Retrospective Studies , Oligopeptides , Gallium Radioisotopes , Kidney Neoplasms/diagnostic imaging , Edetic AcidABSTRACT
PURPOSE: To evaluate parameters derived from 68Ga-PSMA-11 PET/CT images for discriminating pathological characteristics in primary clear-cell renal cell carcinoma (ccRCC). METHODS: The study retrospectively examined data for 36 ccRCC patients with preoperative 68Ga-PSMA-11 PET/CT scan and surgical specimens. Radiological parameters including maximal tumor diameter, mean CT value, and maximal standard uptake value (SUVmax) were derived from PET/CT images. Pathological characteristics included WHO/ISUP grade and adverse pathology (tumor necrosis or sarcomatoid or rhabdoid feature). Values of radiological parameters were compared within subgroups of pathological characteristics. Receiver operating characteristic (ROC) curve analysis was used for the effectiveness of radiological parameters in differentiating pathological characteristics, estimating area under the ROC curve (AUC) and 95% confidence intervals (CIs). RESULTS: The WHO/ISUP grade distribution for 36 tumors was grade 1, 9 (25.0%); grade 2, 12 (33.3%); grade 3, 9 (25.0%); and grade 4, 6 (16.7%). Adverse pathology was positive for 15 (41.7%). Radiological tumor diameter and SUVmax significantly differed by WHO/ISUP grade, pT stage, and adverse pathology (all P < 0.05), with no difference by CT value. Tumor diameter demonstrated sensitivity 86% and specificity 88% for pT stage, with cutoff 6.70 and AUC 0.91 (95% CI, 0.79-1.00, P < 0.001). SUVmax could effectively differentiate WHO/ISUP grade (3-4 vs. 1-2) and adverse pathology (positive vs. negative), with AUC 0.89 (95% CI, 0.81-0.98, P < 0.001), cutoff 16.4, sensitivity 100%, and specificity 71% and AUC 0.92 (95% CI, 0.85-0.99, P < 0.001), cutoff 18.5, sensitivity 94%, and specificity 87%, respectively. CONCLUSION: 68Ga-PSMA-11 PET/CT could effectively identify aggressive pathological features of ccRCC.
