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TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development.

ABSTRACT: TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in established tumor cell lines but not nontransformed cells. Herein, we demonstrate a role for the apoptosis-inducing TRAIL receptor (TRAIL-R) as a metastasis suppressor. Although mouse models employing tumor transplantation have shown that TRAIL can reduce tumor growth, autochthonous tumor models have generated conflicting results with respect to the physiological role of the TRAIL system during tumorigenesis. We used a multistage model of squamous cell carcinoma to examine the role of TRAIL-R throughout all steps of tumor development. DMBA/TPA-treated TRAIL-R-deficient mice showed neither an increase in number or growth rate of benign papillomas nor an increase in the rate of progression to squamous cell carcinoma. However, metastasis to lymph nodes was significantly enhanced, indicating a role for TRAIL-R specifically in the suppression of metastasis. We also found that adherent TRAIL-R-expressing skin carcinoma cells were TRAIL resistant in vitro but were sensitized to TRAIL upon detachment by inactivation of the ERK signaling pathway. As detachment from the primary tumor is an obligatory step in metastasis, this provides a possible mechanism by which TRAIL-R could inhibit metastasis. Hence, treatment of cancer patients with agonists of the apoptosis-inducing receptors for TRAIL may prove useful in reducing the incidence of metastasis.

SUBMITTER: Grosse-Wilde A

PROVIDER: S-EPMC2129237 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Intrahepatic cholangiocarcinoma patients without indications of lymph node metastasis not benefit from lymph node dissection.

Project description:BackgroundTo investigate the necessity of routine lymph node dissection (LND) in intrahepatic cholangiocarcinoma (ICC) patients without indications of lymph node metastasis (LNM) preoperatively.Methods422 consecutive ICC patients who undergone curative resection from January 2009 to December 2014 were enrolled and categorized as two groups (hepatectomy only or hepatectomy plus LND). Clinicopathologic data was compared between the groups by χ2 or Fisher's exact test. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method and differences were analyzed using the log-rank test. Cox regression model was adopted for multivariable analysis.ResultsThe median OS time of all 422 patients was 41.4 months. One-, 3-, and 5-year OS was 67%, 47%, and 35%, respectively. A total of 73 patients had undergone curative resection combined with LND, of whom 20.5% (15/73) were confirmed lymph node positive pathologically. The clinicopathologic characteristics between LND and control groups showed no significant differences. Of the 422 patients, 271 patients had recurrence. The recurrence rates were 65.8% for the LND group and 63.9% for the non-LND group. Survival analysis revealed that, neither the OS (LND vs. non-LND: 32.2 months vs. 46.2 months; p = 0.16) nor the RFS (LND vs. non-LND: 23.1 months vs. 17.0 months; p = 0.09) had significant difference. Multivariate analysis revealed that tumor size, tumor number, carbohydrate antigen19-9, carcinoembryonic antigen, and gamma-glutamyl transpeptidase were independent predictive factors for OS and RFS.ConclusionRoutine LND may not improve survival in resectable ICC patients with negative LNM diagnosis before operation.

| S-EPMC5768365 | biostudies-literature

Integrating No.3 lymph nodes and primary tumor radiomics to predict lymph node metastasis in T1-2 gastric cancer.

Project description:BackgroundThis study aimed to develope and validate a radiomics nomogram by integrating the quantitative radiomics characteristics of No.3 lymph nodes (LNs) and primary tumors to better predict preoperative lymph node metastasis (LNM) in T1-2 gastric cancer (GC) patients.MethodsA total of 159 T1-2 GC patients who had undergone surgery with lymphadenectomy between March 2012 and November 2017 were retrospectively collected and divided into a training cohort (n = 80) and a testing cohort (n = 79). Radiomic features were extracted from both tumor region and No. 3 station LNs based on computed tomography (CT) images per patient. Then, key features were selected using minimum redundancy maximum relevance algorithm and fed into two radiomic signatures, respectively. Meanwhile, the predictive performance of clinical risk factors was studied. Finally, a nomogram was built by merging radiomic signatures and clinical risk factors and evaluated by the area under the receiver operator characteristic curve (AUC) as well as decision curve.ResultsTwo radiomic signatures, reflecting phenotypes of the tumor and LNs respectively, were significantly associated with LN metastasis. A nomogram incorporating two radiomic signatures and CT-reported LN metastasis status showed good discrimination of LN metastasis in both the training cohort (AUC 0.915; 95% confidence interval [CI] 0.832-0.998) and testing cohort (AUC 0.908; 95% CI 0.814-1.000). The decision curve also indicated its potential clinical usefulness.ConclusionsThe nomogram received favorable predictive accuracy in predicting No.3 LNM in T1-2 GC, and the nomogram showed positive role in predicting LNM in No.4 LNs. The nomogram may be used to predict LNM in T1-2 GC and could assist the choice of therapy.

| S-EPMC7989204 | biostudies-literature

Metinel node--the first lymph node draining a metastasis--contains tumor-reactive lymphocytes.

Project description:BACKGROUND: We previously identified tumor-reactive lymphocytes in the first lymph nodes that drain the primary tumor. In this study, we performed lymphatic mapping to investigate the possibility of finding the first lymph nodes that drain metastases, and of learning whether these lymph nodes contained tumor-reactive lymphocytes suitable for adoptive immunotherapy. METHODS: Nineteen patients were studied. The primary tumor site was colorectal cancer in seven patients, malignant melanoma in four, ovarian cancer and breast cancer in two, and one each with pancreatic cancer, cholangiocarcinoma, leiomyosarcoma, and squamous cellular cancer of the tongue. By injection of Patent blue dye or radioactive tracers around the metastases, we identified draining lymph nodes from liver metastases (n = 9), intra-abdominal local recurrences (n = 3), and regional lymph node metastases (n = 7). In six patients, a preoperative lymphoscintigraphy was performed. RESULTS: We located the first draining lymph node or nodes from metastases or local recurrences; we named them "metinel nodes." Lymphocytes from the metinel nodes proliferated, showed clonal expansion, and produced interferon gamma (via in vitro expansions on stimulation with tumor homogenate) and interleukins, all of which demonstrate the characteristics of tumor-reactive lymphocytes. Eight of the nineteen patients received immunotherapy on the basis of tumor-reactive T cells derived from the metinel nodes. CONCLUSIONS: We demonstrate that it is possible to locate the first lymph nodes draining subcutaneous, lymphatic, and visceral metastases, the so-called metinel nodes. Metinel node-derived lymphocytes may be used to treat disseminated solid cancer, and clinical trials should evaluate the effect of such treatment.

| S-EPMC2277445 | biostudies-other

Targeting Lymph Node Sinus Macrophages to Inhibit Lymph Node Metastasis.

Project description:Lymph nodes are important peripheral immune organs in which numerous important immune responses occur. During the process of lymphatic metastasis, lymph nodes are also sites through which tumor cells must pass. Therefore, it is essential to develop a drug delivery system that can specifically transfer immunostimulatory medicine into lymph nodes to block lymphatic metastasis. Here, we developed a nucleic acid drug delivery system containing cationic agarose (C-agarose) and CpG oligodeoxynucleotides. C-agarose has a high affinity for Siglec-1 on the surface of lymph node sinus macrophages, which have a high specificity for targeting lymph nodes. Subcutaneous implantation of C-agarose+CpG gel caused the accumulation of CpG in the lymph node sinus macrophages and generated antitumor immune responses in the lymph node. C-agarose+CpG gel treatment decreased the metastasis size in the tumor-draining lymph node (TDLN) and lung metastatic nodules and suppressed tumor growth in both a mouse 4T1 breast cancer model and a B16F10 melanoma model. On this basis, this study proposes a nonsurgical invasive lymph node targeting immunotherapy concept that may provide a new approach for antitumor metastasis.

| S-EPMC6529739 | biostudies-literature

Predicting Axillary Lymph Node Metastasis in Early Breast Cancer Using Deep Learning on Primary Tumor Biopsy Slides.

Project description:ObjectivesTo develop and validate a deep learning (DL)-based primary tumor biopsy signature for predicting axillary lymph node (ALN) metastasis preoperatively in early breast cancer (EBC) patients with clinically negative ALN.MethodsA total of 1,058 EBC patients with pathologically confirmed ALN status were enrolled from May 2010 to August 2020. A DL core-needle biopsy (DL-CNB) model was built on the attention-based multiple instance-learning (AMIL) framework to predict ALN status utilizing the DL features, which were extracted from the cancer areas of digitized whole-slide images (WSIs) of breast CNB specimens annotated by two pathologists. Accuracy, sensitivity, specificity, receiver operating characteristic (ROC) curves, and areas under the ROC curve (AUCs) were analyzed to evaluate our model.ResultsThe best-performing DL-CNB model with VGG16_BN as the feature extractor achieved an AUC of 0.816 (95% confidence interval (CI): 0.758, 0.865) in predicting positive ALN metastasis in the independent test cohort. Furthermore, our model incorporating the clinical data, which was called DL-CNB+C, yielded the best accuracy of 0.831 (95%CI: 0.775, 0.878), especially for patients younger than 50 years (AUC: 0.918, 95%CI: 0.825, 0.971). The interpretation of DL-CNB model showed that the top signatures most predictive of ALN metastasis were characterized by the nucleus features including density (p = 0.015), circumference (p = 0.009), circularity (p = 0.010), and orientation (p = 0.012).ConclusionOur study provides a novel DL-based biomarker on primary tumor CNB slides to predict the metastatic status of ALN preoperatively for patients with EBC.

| S-EPMC8551965 | biostudies-literature

Predicting lymph node metastasis from primary tumor histology and clinicopathologic factors in colorectal cancer using deep learning.

Project description:BackgroundPresence of lymph node metastasis (LNM) influences prognosis and clinical decision-making in colorectal cancer. However, detection of LNM is variable and depends on a number of external factors. Deep learning has shown success in computational pathology, but has struggled to boost performance when combined with known predictors.MethodsMachine-learned features are created by clustering deep learning embeddings of small patches of tumor in colorectal cancer via k-means, and then selecting the top clusters that add predictive value to a logistic regression model when combined with known baseline clinicopathological variables. We then analyze performance of logistic regression models trained with and without these machine-learned features in combination with the baseline variables.ResultsThe machine-learned extracted features provide independent signal for the presence of LNM (AUROC: 0.638, 95% CI: [0.590, 0.683]). Furthermore, the machine-learned features add predictive value to the set of 6 clinicopathologic variables in an external validation set (likelihood ratio test, p < 0.00032; AUROC: 0.740, 95% CI: [0.701, 0.780]). A model incorporating these features can also further risk-stratify patients with and without identified metastasis (p < 0.001 for both stage II and stage III).ConclusionThis work demonstrates an effective approach to combine deep learning with established clinicopathologic factors in order to identify independently informative features associated with LNM. Further work building on these specific results may have important impact in prognostication and therapeutic decision making for LNM. Additionally, this general computational approach may prove useful in other contexts.

| S-EPMC10125969 | biostudies-literature

Genomic Landscape Alterations in Primary Tumor and Matched Lymph Node Metastasis in Hormone-Naive Prostate Cancer Patients.

Project description:BackgroundProstate cancer (PCa) is a disease with a wide range of clinical manifestations. Up to the present date, the genetic understanding of patients with favorable or unfavorable prognosis is gaining interest for giving the appropriate tailored treatment. We aimed to investigate genetic changes associated with lymph node metastasis in a cohort of hormone-naïve Pca patients.MethodsWe retrospectively analyzed data from 470 patients who underwent surgery for PCa between 2010 and 2020 at the Department of Urology, University of Catania. Inclusion criteria were patients with lymph node metastasis and patients with PCa with extra capsular extension (pT3) and negative lymph node metastasis. The final cohort consisted of 17 different patients (11 PCa with lymph node metastasis and 6 PCa without lymph node metastasis). Through the cBioPortal online tool, we analyzed gene alterations and their correlations with clinical factors.ResultsA total of 688 intronic, synonym and nonsynonym mutations were sequenced. The gene with the most sequenced mutations was ERBB4 (83 mutations, 12% of 688 total), while the ones with the lower percentage of mutations were AKT1, FGFR2 and MLH1 (1 mutation alone, 0.14%).ConclusionIn the present study we found mostly concordance concerning the ERBB4 mutation between both primary PCa samples and matched lymph node metastasis, underlining that the identification of alterations in the primary tumor is extremely important for cancer prognosis prediction.

| S-EPMC9454441 | biostudies-literature

A case report of primary colonic paraganglioma with lymph node metastasis.

Project description:BackgroundParaganglioma is a kind of neuroendocrine tumor that originates from paraganglia outside the adrenal gland. Gastrointestinal tract paraganglioma is very rare and only four cases of paraganglioma originating in the colon have been reported.Case presentationWe report a case of metastatic paraganglioma originating in the colon, in which the differential diagnosis was established by comprehensively considering clinical information, histology, immunohistochemistry, and findings of fluorescence in situ hybridization and next generation sequencing analyses. The patient has remained well for over 14 months after the treatment.ConclusionSince all paraganglioma have metastatic potential, we believe that radical surgical resection and regular follow-up are necessary. Genetic testing may be indicative of metastatic potential and prognosis. Because colonic paraganglioma is very rare, differential diagnosis is very important. Our report provides experience for the diagnosis and study of paraganglioma in rare sites.

| S-EPMC9395918 | biostudies-literature

Differential gene expression in primary breast tumors associated with lymph node metastasis.

Project description:Lymph node status remains one of the most useful prognostic indicators in breast cancer; however, current methods to assess nodal status disrupt the lymphatic system and may lead to secondary complications. Identification of molecular signatures discriminating lymph node-positive from lymph node-negative primary tumors would allow for stratification of patients requiring surgical assesment of lymph nodes. Primary breast tumors from women with negative (n = 41) and positive (n = 35) lymph node status matched for possible confounding factors were subjected to laser microdissection and gene expression data generated. Although ANOVA analysis (P < .001, fold-change >1.5) revealed 13 differentially expressed genes, hierarchical clustering classified 90% of node-negative but only 66% of node-positive tumors correctly. The inability to derive molecular profiles of metastasis in primary tumors may reflect tumor heterogeneity, paucity of cells within the primary tumor with metastatic potential, influence of the microenvironment, or inherited host susceptibility to metastasis.

| S-EPMC3262584 | biostudies-literature

Exploratory analysis of lateral pelvic sentinel lymph node status for optimal management of laparoscopic lateral lymph node dissection in advanced lower rectal cancer without suspected lateral lymph node metastasis.

Project description:BackgroundTotal mesorectal excision (TME) and lateral lymph node dissection (LLND) without radiotherapy (RT) are standard treatment for lower cT3/4 rectal cancers in Eastern countries. In comparative studies, both TME + LLND and RT + TME yield good local control. Although Japanese guidelines recommend LLND for locally advanced rectal cancers below the peritoneal reflection, LLND dissection of clinically negative lateral pelvic lymph nodes (LPLN) is controversial, and laparoscopic TME + LLND is technically challenging and time-consuming. New optical instruments for laparoscopy allow easy perioperative sentinel lymph node (SLN) identification using ICG. The SLN concept may facilitate accurate diagnosis of LPLN involvement, and thus reduce LLND in laparoscopic rectal cancer surgery. Here we investigated lateral pelvic SLN navigation surgery for SLN detection during laparoscopic rectal cancer surgery.MethodsThis study included 21 patients with clinical StageII/III lower rectal cancer without LPLN enlargement, who underwent curative laparoscopic surgery. All patients underwent TME, followed by lateral SLN identification and biopsy using ICG, and then laparoscopic LLND. ICG fluorescence imaging was conducted using the laparoscopic near-infrared camera system.ResultsLateral SLNs were successfully identified in 16 (76.2%) of the 21 patients. Among the 15 patients without SLN tumor metastasis, the dissected lateral non-SLNs were all negative.ConclusionsA lack of metastasis in the lateral pelvic SLN seems to reflect a lack of metastases to all lateral LNs. Our present results suggest that this laparoscopic ICG-guided SLN strategy may be a low-risk and time-saving method to prevent laparoscopic LLND in cases with negative lateral pelvic lymph nodes.

| S-EPMC8356457 | biostudies-literature

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