RESUMEN
BACKGROUND: Large non-apoptotic vesicles released from the plasma membrane protrusions are classified as large-EVs (LEVs). However, the triggers of LEV secretion and their functions in tumors remain unknown. METHODS: Coculture system of cancer cells, peritoneal mesothelial cells (PMCs), and macrophages (MΦs) was conducted to observe cell-cell contact-mediated LEV secretion. Lineage tracing of PMCs was performed using Wt1CreERT2-tdTnu mice to explore the effects of LEVs on PMCs in vivo, and lymphangiogenesis was assessed by qRT-PCR and flow-cytometry. RESULTS: In peritoneal dissemination, cancer cells expressing Ephrin-B (EFNB) secreted LEVs upon the contact with PMCs expressing ephrin type-B (EphB) receptors, which degraded mesothelial barrier by augmenting mesothelial-mesenchymal transition. LEVs were incorporated in subpleural MΦs, and these MΦs transdifferentiated into lymphatic endothelial cells (LEC) and integrated into the lymphatic vessels. LEC differentiation was also induced in PMCs by interacting with LEV-treated MΦs, which promoted lymphangiogenesis. Mechanistically, activation of RhoA-ROCK pathway through EFNB reverse signaling induced LEV secretion. EFNBs on LEVs activated EphB forward signaling in PMC and MΦs, activating Akt, ERK and TGF-ß1 pathway, which were indispensable for causing MMT and LEC differentiation. LEVs accelerated peritoneal dissemination and lymphatic invasions by cancer cells. Blocking of EFNBs on LEVs using EphB-Fc-fusion protein attenuated these events. CONCLUSIONS: EFNBhigh cancer cells scattered LEVs when they attached to PMCs, which augmented the local reactions of PMC and MΦ (MMT and lymphangiogenesis) and exaggerated peritoneal dissemination.
RESUMEN
Gastric cancer (GC) is one of the most common cancers worldwide. Most patients are diagnosed at the progressive stage of the disease, and current anticancer drug advancements are still lacking. Therefore, it is crucial to find relevant biomarkers with the accurate prediction of prognoses and good predictive accuracy to select appropriate patients with GC. Recent advances in molecular profiling technologies, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics, have enabled the approach of GC biology at multiple levels of omics interaction networks. Systemic biological analyses, such as computational inference of "big data" and advanced bioinformatic approaches, are emerging to identify the key molecular biomarkers of GC, which would benefit targeted therapies. This review summarizes the current status of how bioinformatics analysis contributes to biomarker discovery for prognosis and prediction of therapeutic efficacy in GC based on a search of the medical literature. We highlight emerging individual multi-omics datasets, such as genomics, epigenomics, transcriptomics, proteomics, and metabolomics, for validating putative markers. Finally, we discuss the current challenges and future perspectives to integrate multi-omics analysis for improving biomarker implementation. The practical integration of bioinformatics analysis and multi-omics datasets under complementary computational analysis is having a great impact on the search for predictive and prognostic biomarkers and may lead to an important revolution in treatment.
Asunto(s)
Biomarcadores de Tumor , Biología Computacional , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Biomarcadores de Tumor/genética , Biología Computacional/métodos , Pronóstico , Proteómica/métodos , Metabolómica/métodos , Genómica/métodos , Epigenómica/métodosRESUMEN
Background: Breast cancer (BC) has the highest morbidity rate and the second-highest mortality rate of all cancers among women. Recently, multi-cancer genome profiling (multi-CGP) tests have become clinically available. In this study, we aimed to clarify the significance of multi-CGP testing of BC by using the large clinical dataset from The Center for Cancer Genomics and Advanced Therapeutics (C-CAT) profiling database in Japan. Materials and Methods: A total of 3744 BC cases were extracted from the C-CAT database, which enrolled 60,250 patients between June 2019 and October 2023. Of the 3744 BC cases, a total of 3326 cases for which the C-CAT included information on ER, PR, and HER2 status were classified into four subtypes, including TNBC, HR+/HER2-, HR+/HER2+, and HR-/HER2+. Comparisons between groups were performed by the χ2 test or Fisher's exact test using EZR. Kaplan-Meier curves were created using the log-rank test. Results: Of all 3326 cases analyzed, 1114 (33.5%) were TNBC cases, HR+/HER2- accounted for 1787 cases (53.7%), HR+/HER2+ for 260 cases (7.8%), and HR-/HER2+ for 165 cases (5.0%). Genetic abnormalities were most frequently detected in TP53 (58.0%), PIK3CA (35.5%), MYC (18.7%), FGF19 (15.5%), and GATA3 (15.1%) across all BCs. The rate of TMB-High was 12.3%, and the rate of MSI-High was 0.3%, in all BC cases. Therapeutic drugs were proposed for patients with mutations in six genes: PIK3CA, ERBB2, PTEN, FGFR1, ESR1, and AKT1. The prognoses of HR+/HER2- cases were significantly (p = 0.044) better in the treated group than in the untreated group. Conclusions: These findings suggest that cancer gene panel testing is useful for HR+/HER2- cases.
Asunto(s)
Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Femenino , Japón/epidemiología , Persona de Mediana Edad , Neoplasias de la Mama/genética , Receptor ErbB-2/genética , Anciano , Adulto , Estudios Retrospectivos , Biomarcadores de Tumor/genética , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Anciano de 80 o más Años , Pronóstico , Mutación , Perfilación de la Expresión Génica/métodos , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5+. This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin.
Asunto(s)
Neoplasias Colorrectales , Células Epiteliales , Metaplasia , Proteína Quinasa C , Animales , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Proteína Quinasa C/metabolismo , Proteína Quinasa C/genética , Metaplasia/patología , Metaplasia/metabolismo , Ratones , Humanos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Células Madre/metabolismo , Células Madre/patología , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-1/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Proteínas Señalizadoras YAP/metabolismo , Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Organoides/metabolismo , Organoides/patología , Linaje de la Célula , Isoenzimas/metabolismo , Isoenzimas/genética , Isoenzimas/deficiencia , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismoRESUMEN
Connective tissue growth factor (CTGF) is a target gene of the Hippo signaling pathway. Its differential role in the histological types of gastric cancer (GC) remains unknown; therefore, the present study aimed to confirm the clinical significance of CTGF expression in cancer and stromal cells in patients with GC depending on the histological type. The present study enrolled 589 patients with GC. Immunohistochemistry was used to analyze CTGF expression in cancer and stromal cells. CTGF mRNA expression data and the corresponding clinical information of GC samples were collected from The Cancer Genome Atlas (TCGA) database. Subsequently, the associations between CTGF expression and several clinicopathological factors were investigated. In the present study, CTGF expression was mainly observed in the cytoplasm of cancer and stromal cells. CTGF expression in stromal cells was significantly associated with CTGF expression in cancer cells (P<0.001). CTGF positivity in stromal cells was also significantly associated with intestinal type, non-scirrhous type, tumor depth (T1-2), lymph node metastasis (negative), lymphatic invasion (negative) and tumor size (<5 cm). Low CTGF expression in stromal cells was independently associated with worse overall survival (OS). Furthermore, the OS of patients with low CTGF expression in stromal cells, especially in patients with diffuse-type GC, was significantly worse than patients with high CTGF expression (P=0.022). This trend was similar to that revealed by TCGA data analysis. In conclusion, low CTGF expression was associated with a significantly worse OS in patients with diffuse-type GC. These data indicated that CTGF, and its control by the Hippo pathway, may be considered potential treatment targets in diffuse-type GC.
RESUMEN
In recent years, rapid advancement in gene/protein analysis technology has resulted in target molecule identification that may be useful in cancer treatment. Therefore, "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" was published in Japan in September 2021. These guidelines were established to align the clinical usefulness of external diagnostic products with the evaluation criteria of the Pharmaceuticals and Medical Devices Agency. The guidelines were scoped for each tumor, and a clinical questionnaire was developed based on a serious clinical problem. This guideline was based on a careful review of the evidence obtained through a literature search, and recommendations were identified following the recommended grades of the Medical Information Network Distribution Services (Minds). Therefore, this guideline can be a tool for cancer treatment in clinical practice. We have already reported the review portion of "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" as Part 1. Here, we present the English version of each part of the Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition.
Asunto(s)
Biomarcadores de Tumor , Neoplasias , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Japón , Neoplasias/terapia , Neoplasias/genética , Neoplasias/diagnósticoRESUMEN
Purpose: To examine the molecular biological differences between conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma and orbital MALT lymphoma in ocular adnexa lymphoma. Methods: Observational case series. A total of 129 consecutive, randomized cases of ocular adnexa MALT lymphoma diagnosed histopathologically between 2008 and 2020.Total RNA was extracted from formalin-fixed paraffin-embedded tissue from ocular adnexa MALT lymphoma, and RNA-sequencing was performed. Orbital MALT lymphoma gene expression was compared with that of conjunctival MALT lymphoma. Gene set (GS) analysis detecting for gene set cluster was performed in RNA-sequence. Related proteins were further examined by immunohistochemical staining. In addition, artificial segmentation image used to count stromal area in HE images. Results: GS analysis showed differences in expression in 29 GS types in primary orbital MALT lymphoma (N=5,5, FDR q-value <0.25). The GS with the greatest difference in expression was the GS of epithelial-mesenchymal transition (EMT). Based on this GS change, immunohistochemical staining was added using E-cadherin as an epithelial marker and vimentin as a mesenchymal marker for EMT. There was significant staining of vimentin in orbital lymphoma (P<0.01, N=129) and of E-cadherin in conjunctival lesions (P=0.023, N=129). Vimentin staining correlated with Ann Arbor staging (1 versus >1) independent of age and sex on multivariate analysis (P=0.004). Stroma area in tumor were significant difference(P<0.01). Conclusion: GS changes including EMT and stromal area in tumor were used to demonstrate the molecular biological differences between conjunctival MALT lymphoma and orbital MALT lymphoma in ocular adnexa lymphomas.
RESUMEN
Peritoneal dissemination of cancer affects patient survival. The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a microenvironment that promotes cancer cell metastasis in the peritoneum. Here, we investigated the roles of lactosylceramide alpha-2,3-sialyltransferase (ST3G5; also known as ST3GAL5 and GM3 synthase) in the exosome-mediated premetastatic niche in peritoneal milky spots (MSs). Exosomes secreted from ST3G5high cancer cells (ST3G5high -cExos) were found to contain high levels of hypoxia-inducible factor 1-alpha (HIF1α) and accumulated in MSs via uptake in macrophages (MΦs) owing to increased expression of sialic acid-binding Ig-like lectin 1 (CD169; also known as SIGLEC1). ST3G5high -cExos induced pro-inflammatory cytokines and glucose metabolic changes in MΦs, and the interaction of these MΦs with PMCs promoted mesothelial-mesenchymal transition (MMT) in PMCs, thereby generating αSMA+ myofibroblasts. ST3G5high -cExos also increased the expression of immune checkpoint molecules and T-cell exhaustion in MSs, which accelerated metastasis to the omentum. These events were prevented following ST3G5 depletion in cancer cells. Mechanistically, ST3G5high -cExos upregulated chemokines, including CC-chemokine ligand 5 (CCL5), in recipient MΦs and dendritic cells (DCs), which induced MMT and immunosuppression via activation of signal transducer and activator of transcription 3 (STAT3). Maraviroc, a C-C chemokine receptor type 5 (CCR5) antagonist, prevented ST3G5high -cExo-mediated MMT, T-cell suppression, and metastasis in MSs. Our results suggest ST3G5 as a suitable therapeutic target for preventing cExo-mediated peritoneal dissemination.
Asunto(s)
Exosomas , Neoplasias , Humanos , Peritoneo/patología , Exosomas/patología , Comunicación Celular , Transporte Biológico , Neoplasias/patologíaRESUMEN
BACKGROUND/AIM: Multi-cancer genome profiling (multi-CGP) testing intends to predict the therapeutic efficacy of anticancer medication treatments for eligible patients as part of "precision cancer care." The number of cases in which a new treatment was applied based on multi-CGP testing has been reported to be between 10% and 20% for all patients in Japan. This study aimed to determine the significance of multi-CGP testing in Japan by analyzing clinical data from multi-CGP testing in various solid cancers at our Hospital. PATIENTS AND METHODS: A total of 230 patients examined by one of three tests for multi-CGP including NCC Oncopanel, FoundationOne CDx, and FoundationOne Liquid were retrospectively enrolled. Adequate treatment for each patient was discussed at the expert panel meeting according to the results from the genome profiling tests. RESULTS: The most frequent cancer types enrolled in this study were pancreas cancer, bowel cancer, and biliary cancer. Of the 230 cases, 106 (46%) were druggable cases, and 21 (9.1%) were administered medication. Partial response (PR) effect was found in 7 (33.3%) of the 21 cases, of which 3 were biliary cancer and 3 had a BRCA2 mutation. Of all the 21 cases, 7 (33.3%) had the maximum treatment benefit of PR. Three cases of biliary tumors were found in the 7 PR cases within the 21 cases. CONCLUSION: Of 230 patients, 21 were administered medication following multi-CGP testing data, especially frequent in biliary tumor patients. Multi-CGP testing might be particularly beneficial to patients with biliary tumors in Japan.
Asunto(s)
Relevancia Clínica , Neoplasias Pancreáticas , Humanos , Japón , Estudios Retrospectivos , Mutación , HospitalesRESUMEN
Genetic testing has become widespread in daily medical care for gastrointestinal (GI) cancers. However, unlike breast cancer and non-small cell lung cancer, in which personalized medicine targeting various driver genes is standardized, the incidence of targeted gene abnormalities in GI cancers is low. Nevertheless, such abnormalities may be linked to therapeutic agents and the further development of therapeutic agents for personalized medicine for GI cancers is desired. A liquid biopsy is of great benefit in offering clinical decision support, in applications such as GI cancer screening, surgical interventions, monitoring disease status and enhancing patient survival outcomes, all of which would contribute to personalized medicine. Germline genetic testing is required for several types of GI cancer, which shows clinical indications of hereditary predisposition. The increasing use of multigene panel testing has redefined gene-cancer associations, and consequently the estimate of cancer risk that vary from low to high penetrance. Comprehensive genetic testing can enable the detection of novel treatment targets and the discovery of undefined multiple diagnostic/predictive markers, which may enhance the molecular-level understanding of GI cancers. Genetic testing can also aid the design of more appropriate and adequate genomic-driven therapies for patients who may benefit from other standardized therapeutic methods.
RESUMEN
The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
Asunto(s)
Proteína Quinasa C , Transducción de Señal , Animales , Humanos , Ratones , Transformación Celular Neoplásica/genética , Colesterol , Células Epiteliales/metabolismo , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismoRESUMEN
Transforming growth factor-ß (TGF-ß) has attracted attention as a tumor suppressor because of its potent growth-suppressive effect on epithelial cells. Dysregulation of the TGF-ß signaling pathway is considered to be one of the key factors in carcinogenesis, and genetic alterations affecting TGF-ß signaling are extraordinarily common in cancers of the gastrointestinal system, such as hereditary nonpolyposis colon cancer and pancreatic cancer. Accumulating evidence suggests that TGF-ß is produced from various types of cells in the tumor microenvironment and mediates extracellular matrix deposition, tumor angiogenesis, the formation of CAFs, and suppression of the anti-tumor immune reaction. It is also being considered as a factor that promotes the malignant transformation of cancer, particularly the invasion and metastasis of cancer cells, including epithelial-mesenchymal transition. Therefore, elucidating the role of TGF-ß signaling in carcinogenesis, cancer invasion, and metastasis will provide novel basic insight for diagnosis and prognosis and the development of new molecularly targeted therapies for gastrointestinal cancers. In this review, we outline an overview of the complex mechanisms and functions of TGF-ß signaling. Furthermore, we discuss the therapeutic potentials of targeting the TGF-ß signaling pathway for gastrointestinal cancer treatment and discuss the remaining challenges and future perspectives on targeting this pathway.
Asunto(s)
Neoplasias Gastrointestinales , Transducción de Señal , Factor de Crecimiento Transformador beta , Humanos , Carcinogénesis/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factores de Crecimiento Transformadores , Microambiente TumoralRESUMEN
Cancer-associated fibroblasts(CAFs)remodel the extracellular matrix(ECM)and shape the tumor microenvironment (TME), resulting in immune escape and the promotion of tumor metastasis. Using an orthotopic tumor model of colorectal cancers(CRCs)in mice, we demonstrated that the single-cell RNA sequencing of orthotopic rectal tumors identified a subpopulation of CAFs that modulate the immune response. In this review, we report that understanding the role of CAFs in the TME concerning tumor immunity may lead to future avenues for CAF-targeted therapy.
Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias Colorrectales , Animales , Ratones , Fibroblastos Asociados al Cáncer/patología , Neoplasias Colorrectales/patología , Microambiente Tumoral/genética , Fibroblastos/patologíaRESUMEN
INTRODUCTION: Cancer cachexia occurs in cancer patients more frequently as the cancer progresses, with a negative impact on treatment outcomes. In this study, we sought to clarify the clinical impact of a cancer cachexia index (CXI) in patients with gastric cancer (GC) undergoing gastrectomy. METHODS: Between January 2013 and December 2018, we reviewed data from 556 patients treated for GC at our hospital. CXI was calculated using skeletal muscle index (SMI), serum albumin, and neutrophil-lymphocyte ratios (NLR). Patients were divided into high (n = 414) or low CXI (n = 142) groups. We investigated the clinical impact of CXI in patients with GC undergoing gastrectomy. RESULTS: Multivariate analyses of 5-year overall survival (OS) and cancer-specific survival (CSS) rates indicated that a low CXI was independently associated with unfavorable outcomes for patients with GC. In multivariate analyses, SMI was independent predictor of OS but not CSS. NLR was not an independent predictor of either OS or CSS. Complication incidences (≥ Clavien Dindo 3) were non-significantly higher in the low (vs. high) CXI group. CONCLUSION: CXI was a more valuable prognostic biomarker when compared with SMI or NLR in GC patients undergoing gastrectomy. We suggest that patients with low CXI values should be given more comprehensive treatment, including exercise and nutritional therapy to improve clinical outcomes.
Asunto(s)
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/cirugía , Pronóstico , Caquexia/diagnóstico , Caquexia/etiología , Resultado del Tratamiento , Gastrectomía/efectos adversos , Estudios RetrospectivosRESUMEN
Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.
Asunto(s)
Neoplasias Colorrectales , Monocitos , Humanos , Masculino , Animales , Ratones , Terapia de Inmunosupresión , Agresión , Inhibidores de Puntos de Control Inmunológico , Microambiente TumoralRESUMEN
BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) are currently a standard treatment tool for non-small cell lung cancer (NSCLC). RNA-binding motif protein 17 (RBM17), a splicing factor, is frequently over-expressed in NSCLC, but little is known about the role of RBM17 in the efficacy of ICIs for NSCLC. Thus, we investigated the correlation between RBM17 expression and ICI efficacy in NSCLC. PATIENTS AND METHODS: Biopsy or surgical specimens were collected from patients with advanced or recurrent NSCLC who received ICI monotherapy or chemo-immunotherapy in a first-line setting. RBM17 expression was examined using immunohistochemistry. The correlation between the efficacy of ICI monotherapy or chemo-immunotherapy and RBM17 expression was evaluated. RESULTS: Among the 218 cases, 115 (52.8%) cases were positive for RBM17 expression. RBM17 expression was not associated with the objective response rate (ORR) or progression-free survival (PFS) in either of the ICI monotherapy or chemo-immunotherapy groups. However, among those with a low PD-L1 expression level (PD-L1 <50%; n=86), RBM17 expression was significantly associated with a better ORR (p=0.045) and a better PFS (p<0.001) in the ICI monotherapy group, and was significantly associated with a poor ORR in the chemo-immunotherapy group (p=0.041). CONCLUSION: RBM17 might be a useful predictive marker for a higher efficacy of ICI monotherapy in NSCLC patients with a low PD-L1 expression level.
Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Antígeno B7-H1 , Antineoplásicos Inmunológicos/uso terapéutico , Recurrencia Local de Neoplasia , Factores de Empalme de ARNRESUMEN
BACKGROUND/AIM: Intra-tumoral heterogeneity, which is frequently found in various types of cancers, has been suggested to play an important role in cancer progression and metastasis. The findings of our previous study suggested that p-SMAD2 and c-MET signaling might play important roles in the progression to lymph node metastasis of HER2-positive gastric cancer. In this study, we confirmed the effect of SMAD2/MET signaling in the progression of HER2-positive gastric cancer in an animal model. MATERIALS AND METHODS: NCI-N87 cells over-expressing ERBB2, SMAD2, MET were used. To confirm the role of SMAD2 and MET expression on lymph node metastasis of gastric cancer, we orthotopically injected NCI-N87 cells with or without the knockdown of both SMAD2 and MET into the gastric walls of BALBc nude mice. RESULTS: The number of metastatic lymph nodes was significantly smaller in the knockdown group compared to that in the control group. However, there was no significant difference in gastric tumor size between the two groups. CONCLUSION: SMAD2 and MET signaling might play important roles specifically in the progression to lymph node metastasis of HER2-positive gastric cancer. c-MET and SMAD2 may be useful targets for preventing lymph node metastasis in patients with HER2-positive gastric cancer.
Asunto(s)
Neoplasias Gástricas , Animales , Ratones , Humanos , Metástasis Linfática/patología , Neoplasias Gástricas/patología , Ratones Desnudos , Ganglios Linfáticos/patología , Estudios Retrospectivos , Proteína Smad2/genética , Proteína Smad2/metabolismoRESUMEN
MicroRNAs (miRNAs) play pivotal roles in the tumor microenvironment. Here, we analyzed miRNAs in tumor stromal fibroblasts. Expression of miR-224-3p in cancer-associated fibroblasts (CAF) from scirrhous gastric cancer patients was lower than in normal fibroblasts (NF). Introduction of a miR-224-3p mimic attenuated migration and invasion of CAF. Coiled-coil domain containing 85A (CCDC85A), whose function in tumors is not understood, was the target gene of miR-224-3p. Immunohistological analysis revealed that CCDC85A is expressed to varying degrees by cancer cells and CAFs in gastric and pancreatic carcinomas. Downregulation of CCDC85A in cancer cells revealed that these cells are vulnerable to endoplasmic reticulum (ER) stress induced by thapsigargin or tunicamycin, which were ameliorated after addback of CCDC85A. Injection of NF-derived exosomes containing miR-224-3p into the xenograft tumor increased tumor shrinkage by cisplatin treatment. Mechanistically, CCDC85A associated with the molecular chaperone GRP78 and GRP94, thereby inhibiting association of these negative regulators of the unfolded protein response (UPR), leading to sustained activation of PERK and downstream eIF2ã and ATF4 upon ER stress. These data suggest a novel miR-224-3p-mediated function for CCDC85A: protection from ER stress and cisplatin resistance.
RESUMEN
The expression of trophoblast cell surface antigen-2 (Trop-2) is enhanced in many tumor tissues and is correlated with increased malignancy and poor survival of patients with cancer. Previously, we demonstrated that the Ser-322 residue of Trop-2 is phosphorylated by protein kinase Cα (PKCα) and PKCδ. Here, we demonstrate that phosphomimetic Trop-2 expressing cells have markedly decreased E-cadherin mRNA and protein levels. Consistently, mRNA and protein of the E-cadherin-repressing transcription factors zinc finger E-Box binding homeobox 1 (ZEB1) were elevated, suggesting transcriptional regulation of E-cadherin expression. The binding of galectin-3 to Trop-2 enhanced the phosphorylation and subsequent cleavage of Trop-2, followed by intracellular signaling by the resultant C-terminal fragment. Binding of ß-catenin/transcription factor 4 (TCF4) along with the C-terminal fragment of Trop-2 to the ZEB1 promoter upregulated ZEB1 expression. Of note, siRNA-mediated knockdown of ß-catenin and TCF4 increased the expression of E-cadherin through ZEB1 downregulation. Knockdown of Trop-2 in MCF-7 cells and DU145 cells resulted in downregulation of ZEB1 and subsequent upregulation of E-cadherin. Furthermore, wild-type and phosphomimetic Trop-2 but not phosphorylation-blocked Trop-2 were detected in the liver and/or lung of some nude mice bearing primary tumors inoculated intraperitoneally or subcutaneously with wild-type or mutated Trop-2 expressing cells, suggesting that Trop-2 phosphorylation, plays an important role in tumor cell mobility in vivo, too. Together with our previous finding of Trop-2 dependent regulation of claudin-7, we suggest that the Trop-2-mediated cascade involves concurrent derangement of both tight and adherence junctions, which may drive metastasis of epithelial tumor cells.