ABSTRACT
RNA modifications, including the renowned m6A, have recently garnered significant attention. This chemical alteration, present in mRNA, exerts a profound influence on protein expression levels by affecting splicing, nuclear export, stability, translation, and other critical processes. Although the role of RNA methylation in the pathogenesis and progression of IBD and colorectal cancer has been reported, many aspects remain unresolved. In this comprehensive review, we present recent studies on RNA methylation in IBD and colorectal cancer, with a particular focus on m6A and its regulators. We highlight the pivotal role of m6A in the pathogenesis of IBD and colorectal cancer and explore the potential applications of m6A modifications in the diagnosis and treatment of these diseases.
Subject(s)
Colorectal Neoplasms , Inflammatory Bowel Diseases , Humans , RNA Methylation , Inflammatory Bowel Diseases/genetics , RNA Splicing/genetics , RNA, Messenger/genetics , Colorectal Neoplasms/genetics , RNAABSTRACT
Bromodomain and extraterminal domain (BET) family proteins are epigenetic master regulators of gene expression via recognition of acetylated histones and recruitment of transcription factors and co-activators to chromatin. Hence, BET family proteins have emerged as promising therapeutic targets in cancer. In this study, we examined the functional role of bromodomain containing 3 (BRD3), a BET family protein, in colorectal cancer (CRC). In vitro and vivo analyses using BRD3-knockdown or BRD3-overexpressing CRC cells showed that BRD3 suppressed tumor growth and cell cycle G1/S transition and induced p21 expression. Clinical analysis of CRC datasets from our hospital or The Cancer Genome Atlas revealed that BET family genes, including BRD3, were overexpressed in tumor tissues. In immunohistochemical analyses, BRD3 was observed mainly in the nucleus of CRC cells. According to single-cell RNA sequencing in untreated CRC tissues, BRD3 was highly expressed in malignant epithelial cells, and cell cycle checkpoint-related pathways were enriched in the epithelial cells with high BRD3 expression. Spatial transcriptomic and single-cell RNA sequencing analyses of CRC tissues showed that BRD3 expression was positively associated with high p21 expression. Furthermore, overexpression of BRD3 combined with knockdown of, a driver gene in the BRD family, showed strong inhibition of CRC cells in vitro. In conclusion, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression. BRD3 activation might be a novel therapeutic approach for CRC.
Subject(s)
Colorectal Neoplasms , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Transcription Factors , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Animals , Mice , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cell Proliferation/genetics , Female , Male , Bromodomain Containing ProteinsABSTRACT
BACKGROUND: Intratumor heterogeneity (ITH) in microsatellite instability-high (MSI-H) colorectal cancer (CRC) has been poorly studied. We aimed to clarify how the ITH of MSI-H CRCs is generated in cancer evolution and how immune selective pressure affects ITH. METHODS: We reanalyzed public whole-exome sequencing data on 246 MSI-H CRCs. In addition, we performed a multi-region analysis from 6 MSI-H CRCs. To verify the process of subclonal immune escape accumulation, a novel computational model of cancer evolution under immune pressure was developed. RESULTS: Our analysis presented the enrichment of functional genomic alterations in antigen-presentation machinery (APM). Associative analysis of neoantigens indicated the generation of immune escape mechanisms via HLA alterations. Multiregion analysis revealed the clonal acquisition of driver mutations and subclonal accumulation of APM defects in MSI-H CRCs. Examination of variant allele frequencies demonstrated that subclonal mutations tend to be subjected to selective sweep. Computational simulations of tumour progression with the interaction of immune cells successfully verified the subclonal accumulation of immune escape mutations and suggested the efficacy of early initiation of an immune checkpoint inhibitor (ICI) -based treatment. CONCLUSIONS: Our results demonstrate the heterogeneous acquisition of immune escape mechanisms in MSI-H CRCs by Darwinian selection, providing novel insights into ICI-based treatment strategies.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Humans , Microsatellite Instability , Colorectal Neoplasms/pathology , Colonic Neoplasms/genetics , Mutation , Antigen Presentation , Microsatellite Repeats/geneticsABSTRACT
A female in her 70s underwent right hepatectomy with resection of caudate lobe and extrahepatic bile duct for perihilar cholangiocarcinoma(T2aN0M0, Stage â ¡: Biliary Cancer Treatment Regulations, 7th edition). On the 4th postoperative day, the patient had impaired consciousness, which worsened to almost coma on the 5th postoperative day. On the same day, a blood test showed high ammonia level, thus the state was thought to be hepatic encephalopathy. Contrast -enhanced CT on the same day showed thrombus from the main trunk of the portal vein to the remnant left branch, narrowing of the lumen of the vessel. Simultaneously, enlarged portosystemic shunt in the pelvic floor due to portal hypertension induced by the thrombosis. Plasmapheresis was performed, and anticoagulation with sodium heparin and antithrombin â ¢ were started. Then, the portal vein thrombus was reduced, and encephalopathy was improved. She was discharged from the hospital on postoperative day 48. She was treated with edoxaban as an outpatient, and anticoagulation therapy was terminated after a CT scan 6 months after surgery, which confirmed no recurrence of thrombus. She is now alive without recurrence of thrombus or tumor for about 2 years after the surgery.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Hepatic Encephalopathy , Klatskin Tumor , Liver Diseases , Thrombosis , Female , Humans , Bile Duct Neoplasms/complications , Bile Duct Neoplasms/surgery , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Cholangiocarcinoma/surgery , Hepatectomy , Hepatic Encephalopathy/etiology , Klatskin Tumor/surgery , Liver Diseases/pathology , Liver Diseases/surgery , Portal Vein/surgery , Portal Vein/pathology , Thrombosis/surgery , AgedABSTRACT
74-year-old woman was diagnosed with locally advanced unresectable transverse colon cancer. She started CAPOX therapy as first-line therapy after ileostomy. After second course, MSI-high was detected, so nivolumab plus ipilimumab combination therapy was started as second-line therapy. After 4 courses of combination therapy, she was judged to be in partial response and surgery was performed. Histopathological diagnosis of the surgical specimen showed complete response, and she is still alive without recurrence 15 months after surgery.
Subject(s)
Colon, Transverse , Colonic Neoplasms , Female , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/drug therapy , Colonic Neoplasms/surgery , Ipilimumab , Nivolumab/therapeutic use , AgedABSTRACT
A 80s man was diagnosed circulated type 2 colon cancer at the transverse colon, and pathological findings was adenocarcinoma( por1). Genomic findings were microsatellite instability-high(MSI-H), all RAS wild type and BRAFV600E mutated. Contrast-enhanced CT showed an enlarged lymph nodes(#221, #222, #223, #214)along the middle colic and superior mesenteric artery. Clinical diagnosis was a locally advanced unresectable transverse colon cancer, cT4aN3M1a(LYM), cStage â £a. Drug therapy with pembrolizumab was prescribed. Six months later, contrast-enhanced CT and PET demonstrated remarkable shrinkage of the primary tumor and lymph nodes except 2 peri-colic enlarged lymph nodes. Primary lesion turned almost undetectable, however the biopsy demonstrated residual tumor. Two months later, CT showed that the residual lymph nodes had also disappeared.
Subject(s)
Colic , Colon, Transverse , Colonic Neoplasms , Humans , Male , Colic/pathology , Colon, Transverse/surgery , Colon, Transverse/pathology , Colonic Neoplasms/drug therapy , Colonic Neoplasms/surgery , Colonic Neoplasms/genetics , Lymph Nodes/pathology , Microsatellite Instability , Aged, 80 and overABSTRACT
We report a case of locally advanced rectal cancer that could not be curatively resected, in which the patient underwent conversion surgery after chemotherapy. The patient is a 70-year-old woman. She came to our hospital with a chief complaint of lower abdominal pain, and a close examination revealed rectal cancer with invasion of the external iliac artery and pelvic wall. She was treated with mFOLFOX6 plus cetuximab for locally advanced rectal cancer that was not amenable to surgical resection. After 11 courses of chemotherapy, significant shrinkage of the tumor was observed, and robot assisted laparoscopic high-anterior resection was performed. The patient didn't relapse at 12 months after surgery without adjuvant chemotherapy.
Subject(s)
Laparoscopy , Rectal Neoplasms , Female , Humans , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/surgery , Rectal Neoplasms/drug therapy , Rectal Neoplasms/surgery , Rectal Neoplasms/pathology , Chemotherapy, AdjuvantABSTRACT
Microtubules are among the most successful targets for anticancer therapy because they play important roles in cell proliferation as they constitute the mitotic spindle, which is critical for chromosome segregation during mitosis. Hence, identifying new therapeutic targets encoding proteins that regulate microtubule assembly and function specifically in cancer cells is critical. In the present study, we identified a candidate gene that promotes tumor progression, ribonucleic acid export 1 (RAE1), a mitotic checkpoint regulator, on chromosome 20q through a bioinformatics approach using datasets of colorectal cancer (CRC), including The Cancer Genome Atlas (TCGA). RAE1 was ubiquitously amplified and overexpressed in tumor cells. High expression of RAE1 in tumor tissues was positively associated with distant metastasis and was an independent poor prognostic factor in CRC. In vitro and in vivo analysis showed that RAE1 promoted tumor growth, inhibited apoptosis, and promoted cell cycle progression, possibly with a decreased proportion of multipolar spindle cells in CRC. Furthermore, RAE1 induced chemoresistance through its anti-apoptotic effect. In addition, overexpression of RAE1 and significant effects on survival were observed in various types of cancer, including CRC. In conclusion, we identified RAE1 as a novel gene that facilitates tumor growth in part by inhibiting apoptosis and promoting cell cycle progression through stabilizing spindle bipolarity and facilitating tumor growth. We suggest that it is a potential therapeutic target to overcome therapeutic resistance of CRC.
Subject(s)
Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm , Gene Amplification , Nuclear Matrix-Associated Proteins/genetics , Nucleocytoplasmic Transport Proteins/genetics , Up-Regulation , Aged , Animals , Caco-2 Cells , Cell Cycle , Cell Line, Tumor , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Databases, Genetic , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Middle Aged , Paclitaxel , PrognosisABSTRACT
A female patient in her 60s was diagnosed with advanced gallbladder cancer invading the hilar plate. Exploratory laparoscopic examination showed limited peritoneal dissemination. Despite endoscopic nasobiliary drainage, it was difficult to treat infectious cholangitis. To initiate chemotherapy, it was imperative to control the infection; hence, we chose to perform extended right hepatectomy, extrahepatic bile duct resection, lymph node dissection, and cholangiojejunostomy. We have been able to continue systemic chemotherapy for more than 2 years after surgery, and the patient did not experience infectious cholangitis. She has survived for almost 2 years and 8 months post-diagnosis.
Subject(s)
Bile Ducts, Extrahepatic , Gallbladder Neoplasms , Female , Hepatectomy , Humans , Lymph Node Excision , PrognosisABSTRACT
BACKGROUND: Neoadjuvant chemotherapy is designed to prevent disease recurrence, particularly distant recurrence, and to improve overall patient survival. We present 2 cases where pathological complete response(pCR)was obtained after administering XELOXIRI as neoadjuvant chemotherapy for locally advanced rectal cancer. Case 1: The patient was a 63-year-old man diagnosed with rectal cancer(Ra, cT4aN1M0, cStage â ¢a)and treated with 6 courses of XELOXIRI as neoadjuvant chemotherapy. After systemic chemotherapy, he underwent laparoscopy-assisted low anterior resection and showed a pCR. Case 2: The patient was a 56-year-old man diagnosed with rectal cancer(Rb, cT3N3M0, cStage â ¢b)and treated with 6 couses of XELOXIRI as neoadjuvant chemotherapy. After systemic chemotherapy, he underwent low anterior resection and showed a pCR. CONCLUSION: We present 2 cases treated with XELOXIRI as neoadjuvant chemotherapy for locally advanced rectal cancer where pCRwas achieved.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoadjuvant Therapy , Rectal Neoplasms , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Rectal Neoplasms/therapy , RectumABSTRACT
A 61-year-old man complainingof bloody stool was diagnosed with advanced rectal cancer with multiple liver metastases (cT3[A]N1M1a[H2], cStage â £). We introduced bevacizumab combined systemic chemotherapy prior to radical surgery and confirmed tumor shrinkage in both the primary tumor and liver metastases following systemic chemotherapy. We performed laparoscopic lower-anterior resection, and then the patient underwent liver metastases resection. The histologic evaluation was Grade 2. This was a pathologically curative resection, and the patient has been disease-free since the last operation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Liver Neoplasms , Rectal Neoplasms , Bevacizumab , Hepatectomy , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Male , Middle Aged , Rectal Neoplasms/drug therapy , Rectal Neoplasms/surgeryABSTRACT
A 76-year-old woman complaining of constipation was diagnosed with advanced rectosigmoid colon cancer with unresectable liver metastases. We performed a laparoscopic high-anterior resection due to the obstruction. The patient then received a capecitabine plus oxaliplatin(CapeOX)plus cetuximab(Cmab)combination chemotherapy. After 7 cycles of CapeOX with Cmab, the multiple liver metastases had reduced remarkably in size. Therefore, a liver metastases resection was performed. The patient underwent 6 cycles of postoperative CapeOX with Cmab therapy and has survived 7 years with no recurrence after the primary surgery.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms , Liver Neoplasms , Molecular Targeted Therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/surgery , Female , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Neoplasm Recurrence, LocalABSTRACT
We report a case of long-term survival without recurrence followingresection of hepatic and pulmonary metastases of gastric cancer. A 64-year-old man underwent distal gastrectomy for gastric cancer. Seventeen months later, he underwent partial hepatectomy for hepatic metastasis in S7. Twenty months after the partial hepatectomy, he underwent hepatectomy for right lobe resection for hepatic metastases in S6/S7 and S7. Six months after the hepatectomy, he underwent partial pulmonary resection for lungmetastasis in the right lung(S3). He has remained tumor-free for 5 years after the pulmonary resection.
Subject(s)
Liver Neoplasms , Lung Neoplasms , Stomach Neoplasms , Hepatectomy , Humans , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Lung Neoplasms/secondary , Lung Neoplasms/surgery , Male , Middle Aged , Neoplasm Recurrence, Local , Stomach Neoplasms/pathology , Stomach Neoplasms/surgeryABSTRACT
We reported 2 cases of hepatic encephalopathy after chemotherapy for advanced colorectal cancer. Case 1: A 49-year-old male was diagnosed advanced sigmoid colon cancer with peritoneal dissemination, multiple liver metastasis and multiple osseous metastasis. After resection of primary lesion, we administered mFOLFOX6 plus bevacizumab combination therapy. He was in comatose(Japan coma scale 200)3 days after 2 courses of administration of this regimen. Case 2: A 57-year-old female was diagnosed advanced rectal cancer with multiple huge liver metastasis and multiple osseous metastasis. We administered mFOLFOX6 plus panitumumab combination therapy. She was in comatose(Japan coma scale 100)3 days after 10 courses of administration of this regimen. In both cases, radiographic imaging showed no abnormal sign and blood examination revealed a high level of serum ammonia. We diagnosed their disturbance of consciousness as a symptom of hepatic encephalopathy. Branched-chain amino acid infusion rapidly improved disturbance of consciousness. We must consider the symptom, hepatic encephalopathy in patients receiving chemotherapy for advanced colorectal cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Hepatic Encephalopathy/chemically induced , Liver Neoplasms/drug therapy , Rectal Neoplasms/drug therapy , Sigmoid Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Humans , Liver Neoplasms/secondary , Male , Middle Aged , Rectal Neoplasms/pathology , Rectal Neoplasms/surgery , Sigmoid Neoplasms/pathology , Sigmoid Neoplasms/surgeryABSTRACT
The patient, a 76-year-old man, presented to his local doctor's clinic with complaints of fatigue and lightheadedness. Because blood test results indicated anemia, he was referred to our hospital. Upper gastrointestinal endoscopy indicated a type 2 tumor of approximately 5 cm at the top of the gastric corpus. Biopsy results indicated that the lesion was a poorly differentiated adenocarcinoma. Computed tomography showed multiple liver metastases and the patient was diagnosed with stage â £ gastric cancer. After a blood transfusion, chemotherapy with S-1 was started. However, as the patient experienced continued hemorrhage from the primary lesion, treatment was changed to total gastrectomy in order to control the bleeding. The pathologic examination of the resected specimen indicated that the tumor was located in the muscle and subserosal layers. The tumor cells were spindle-shaped, c-kit positive, cytokeratin-negative, and Dog-1 positive. Therefore, a diagnosis of gastrointestinal stromal tumor (GIST) was made. Postoperatively, chemotherapy with imatinib was administered and the patient was alive with no progression of disease 1 year following surgery. Intraductal growth pattern GISTs of the stomach that protrude into the epithelium and exhibit ulceration can be difficult to distinguish from gastric carcinomas. We experienced a case of gastric GIST that was difficult to diagnose preoperatively.
Subject(s)
Gastrointestinal Stromal Tumors , Stomach Neoplasms/pathology , Aged , Antineoplastic Agents/therapeutic use , Biopsy , Drug Combinations , Gastrectomy , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/secondary , Gastrointestinal Stromal Tumors/surgery , Humans , Imatinib Mesylate/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Male , Oxonic Acid/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery , Tegafur/therapeutic useABSTRACT
BACKGROUND: Cardiac tamponade is a rare postoperative complication of esophageal cancer surgery, which leads to rapid hemodynamic changes and can be fatal if not treated properly and promptly. Herein, we report a case of cardiac tamponade after thoracoscopic subtotal esophagectomy and retrosternal gastric tube reconstitution for esophageal cancer that was successfully treated with surgical drainage. CASE PRESENTATION: An 86-year-old man with lower thoracic esophageal cancer underwent thoracoscopic subtotal esophagectomy and retrosternal gastric tube reconstitution. No intra-operative complications were observed. On the first postoperative day, tachycardia and hypotension were observed, and pericardial effusion was identified on computed tomography images. The patient was diagnosed with obstructive shock secondary to cardiac tamponade. As percutaneous puncture drainage was not possible due to the presence of a retrosternal gastric tube, pericardiotomy with a small left anterior thoracotomy was performed, and a large amount of hematogenous fluid was drained, which instantly improved circulation. On the second postoperative day, the patient showed decreased pulse pressure, and computed tomography revealed a residual and enlarged hematoma around the right ventricle. The patient underwent surgical drainage and another pericardiotomy with a small right anterior thoracotomy was performed to drain the hematoma. At this time, multiple injuries to the fatty tissue, epicardium, and myocardium with active bleeding were observed on the anterior surface of the right ventricle near the root of the pulmonary artery. In this patient, the ascending aorta ran further to the right and dorsal sides than usual, causing the anterior wall of the right ventricle near the root of the pulmonary artery to be closer to the back of the sternum. This abnormality may have contributed to injury during the creation of the retrosternal pathway, leading to cardiac tamponade. CONCLUSIONS: Cardiac tamponade after esophagectomy can occur because of manipulation during creation of the retrosternal route, with an anomaly in the aortic position being present in this case. Gentle manipulation and selection of the reconstruction route according to the patient's condition are necessary in cases with such anatomical abnormalities.
ABSTRACT
BACKGROUND: APC and MUTYH are both well-known colorectal polyposis causative genes. However, 30-50% of colorectal adenomatous polyposis cases are classified as colonic adenomatous polyposis of unknown etiology and lack identifiable pathogenic variants. Although guidelines recommend total proctocolectomy for colonic adenomatous polyposis of unknown etiology with over 100 adenomas, evidence is lacking. This study presents a unique case of localized colonic adenomatous polyposis of unknown etiology with multiple adenocarcinomas, treated with hemicolectomy and regional lymph node dissection. CASE PRESENTATION: The patient was a 72-year-old woman whose colonoscopy revealed numerous polyps and two adenocarcinomas localized in the right side of the colon, with no lesions in the left side. The patient had no family history of polyposis or colorectal cancer. No extracolonic lesions, enlarged lymph nodes, or distant metastases were found. Considering the patient's age and lesion localization, laparoscopic right hemicolectomy with regional lymph node dissection was performed. Histopathological diagnosis revealed three adenocarcinoma lesions with no lymph node metastasis. The most advanced pathological stage was T2N0M0 Stage I (UICC 8th edition). The patient was alive 5 years postoperatively, without recurrence of cancer or polyposis in the remaining colon and rectum. To diagnose hereditary colorectal cancer/polyposis, a germline multigene panel testing for APC, EPCAM, MBD4, MLH1, MLH3, MSH2, MSH3, MSH6, MUTYH, NTHL1, PMS2, POLD1, POLE, and TP53 was performed using DNA extracted from blood samples: however, no pathogenic variant was detected. Therefore, the patient was diagnosed with colonic adenomatous polyposis of unknown etiology. CONCLUSIONS: In this rare case, colonic adenomatous polyposis of unknown etiology, with numerous adenomatous polyps and multiple adenocarcinomas localized in the right side of the colon, was successfully treated with right hemicolectomy and regional lymph node dissection. Despite genetic analysis, no causative germline variants were identified. Segmental colectomy according to the distribution of polyps might be a curative approach.
ABSTRACT
BACKGROUND: Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. METHODS: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. FINDINGS: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. INTERPRETATION: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. FUNDING: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.
Subject(s)
Colorectal Neoplasms , Midkine , Single-Cell Analysis , T-Lymphocytes, Regulatory , Tumor Microenvironment , Female , Humans , Male , Carcinogenesis/genetics , Carcinogenesis/immunology , Cell Communication/immunology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/mortality , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Immune Tolerance , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transcriptome , Tumor Microenvironment/immunology , Midkine/immunology , Midkine/metabolismABSTRACT
BACKGROUND/AIM: Peritoneal metastasis (PM) of gastric cancer (GC) leads to poor clinical outcomes. Tumor-derived exosomes promote metastasis via communication between tumor cells and host cells. In this study, we investigated the effect of Rab27, which is required for exosome secretion, on the PM of GC. MATERIALS AND METHODS: We established a stable knockdown of two Rab27 homologs, Rab27a and Rab27b, in human GC cells (58As9) with a high potential of PM. We examined the level of exosome secretion from Rab27-knockdown 58As9 cells by Western blotting and the ability of Rab27b knockdown to suppress PM in 58As9 cells using a mouse xenograft model. In vitro proliferation and invasion assays were performed in the Rab27b-knockdown cells. Next, Rab27b expression was evaluated in human GC tissues by immunohistochemistry. Finally, we assessed the clinicopathological and prognostic significance of Rab27b expression by RT-qPCR in both our and other TCGA datasets of GC. RESULTS: Rab27a and Rab27b knockdown in 58As9 cells decreased the secretion of exosomes, characterized by the endocytic marker CD63. Rab27b knockdown decreased PM in vivo without affecting the in vitro proliferation or invasion ability of 58As9 cells. In human GC tissues, Rab27b was overexpressed in tumor cells. The overall and recurrence-free survival rates were significantly lower in GC patients with high compared to low Rab27b mRNA expression in our and other TCGA datasets. CONCLUSION: Rab27b expression potentially serves as a poor prognostic biomarker, possibly affecting PM via exosome secretion from GC cells.
Subject(s)
Exosomes , Peritoneal Neoplasms , Stomach Neoplasms , rab27 GTP-Binding Proteins , Humans , Cell Line, Tumor , Exosomes/genetics , Exosomes/metabolism , Peritoneal Neoplasms/genetics , Peritoneal Neoplasms/metabolism , rab GTP-Binding Proteins/genetics , rab GTP-Binding Proteins/metabolism , rab27 GTP-Binding Proteins/genetics , rab27 GTP-Binding Proteins/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/pathologyABSTRACT
The cellular interactions in the tumor microenvironment of colorectal cancer (CRC) are poorly understood, hindering patient treatment. In the current study, we investigate whether events occurring at the invasion front are of particular importance for CRC treatment strategies. To this end, we analyze CRC tissues by combining spatial transcriptomics from patients with a public single-cell transcriptomic atlas to determine cell-cell interactions at the invasion front. We show that CRC cells are localized specifically at the invasion front. These cells induce human leukocyte antigen G (HLA-G) to produce secreted phosphoprotein 1 (SPP1)+ macrophages while conferring CRC cells with anti-tumor immunity, as well as proliferative and invasive properties. Taken together, these findings highlight the signaling between CRC cell populations and stromal cell populations at the cellular level.