RESUMO
Recent cancer genome analyses have identified frequently mutated genes that are responsible for the development and malignant progression of cancers, including colorectal cancer (CRC). We previously constructed mouse models that carried major driver mutations of CRC, namely Apc, Kras, Tgfbr2, Trp53, and Fbxw7, in combinations. Comprehensive histological analyses of the models showed a link between mutation combinations and malignant phenotypes, such as invasion, epithelial-mesenchymal transition (EMT), and metastasis. The major cause of cancer-related death is metastasis, making it important to understand the mechanism underlying metastasis in order to develop novel therapeutic strategies. To this end, we have established intestinal tumor-derived organoids from different genotyped mice and generated liver metastasis models via transplantation of the organoids into the spleen. Through histological and imaging analyses of the transplantation models, we have determined that the combination of Apc, Kras, Tgfbr2, and Trp53 mutations promotes liver metastasis at a high incidence. We also demonstrated polyclonal metastasis of tumor cell clusters consisting of genetically and phenotypically distinct cells through our model analysis. These organoid transplantation models recapitulate human CRC metastasis, constituting a useful tool for basic and clinical cancer research as a preclinical model. We herein report the experimental protocols of the organoid culture and generation of metastasis models.
Assuntos
Neoplasias Hepáticas , Mutação , Organoides , Animais , Organoides/patologia , Camundongos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Genótipo , Modelos Animais de Doenças , Proteína Supressora de Tumor p53/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Metástase Neoplásica , Humanos , Proteína da Polipose Adenomatosa do Colo/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Transição Epitelial-Mesenquimal/genéticaRESUMO
BACKGROUND Perivascular epithelioid cell tumor (PEComa) is usually a benign perivascular tumor that expresses both melanocytic and myogenic cell markers. We report 2 cases of advanced malignant uterine perivascular epithelioid cell tumor (PEComa) in a 74-year-old woman and a 50-year-old woman undergoing surgery in our center. CASE REPORT Case 1: A 74-year-old woman presented with a painful and massive abdominal mass. The imaging revealed a 19-cm necrotic mass close to the mesentery, a suspicious lesion in the uterus, and a probable liver metastasis. The pathological diagnosis was quite difficult with mixed features of leiomyosarcoma and PEComa with an uncommon immunohistochemistry staining pattern. Therefore, we gave a diagnosis of sarcoma with PEComa-like features. Case 2: A 50-year-old woman with metrorrhagia and abdominal pain. Imaging revealed a 7-cm mass in the uterus and suspicious metastatic lesions in the lung and the liver. The immunohistochemistry pattern was typical, with a strong positivity of Human Melanoma Black-45 (HMB-45) and focal positivity of H-Caldesmon. The patient benefited from targeted adjuvant therapy (MTOR inhibitor-based), with 8-month a follow-up showing no recurrence for this Grade IV PEComa mutated for TP53, ATRX, and TSC1. CONCLUSIONS We have report 2 cases of metastatic PEComa with different clinicopathological features. An overlap remains between characteristics of PEComas and smooth-muscle tumors. At present, there are no known pathognomonic findings or specific diagnostic markers.
Assuntos
Neoplasias de Células Epitelioides Perivasculares , Neoplasias Uterinas , Humanos , Feminino , Neoplasias de Células Epitelioides Perivasculares/diagnóstico , Neoplasias de Células Epitelioides Perivasculares/secundário , Neoplasias de Células Epitelioides Perivasculares/patologia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologia , Pessoa de Meia-Idade , Idoso , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/diagnóstico , Diagnóstico Diferencial , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundárioRESUMO
PURPOSE: Liver was one of the most common distant metastatic sites in breast cancer. Patients with distant metastasis were identified as American Joint Committee on Cancer (AJCC) stage IV indicating poor prognosis. However, few studies have predicted the survival in females with T1-2N0-1 breast cancer who developed liver metastasis. This study aimed to explore the clinical features of these patients and establish a nomogram to predict their overall survival. RESULTS: 1923 patients were randomly divided into training (n = 1154) and validation (n = 769) cohorts. Univariate and multivariate analysis showed that age, marital status, race, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), chemotherapy, surgery and bone metastasis, brain metastasis were considered the independent prognostic indicators. We developed a nomogram according to these ten parameters. The consistency index (c-index) was 0.72 (95% confidence interval CI 0.70-0.74) in the training cohort, 0.72 (95% CI 0.69-0.74) in the validation cohort. Calibration plots indicated that the nomogram-predicted survival was consistent with the recorded 1-, 3- and 5-year prognoses. Decision curve analysis curves in both the training and validation cohorts demonstrated that the nomogram showed better prediction than the AJCC TNM (8th) staging system. Kaplan Meier curve based on the risk stratification system showed that the low-risk group had a better prognosis than the high-risk group (P < 0.001). CONCLUSIONS: A predictive nomogram and risk stratification system were constructed to assess prognosis in T1-2N0-1 breast cancer patients with liver metastasis in females. The risk model established in this study had good predictive performance and could provide personalized clinical decision-making for future clinical work.
Assuntos
Neoplasias da Mama , Neoplasias Hepáticas , Nomogramas , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Medição de Risco , Adulto , Análise de Sobrevida , Estadiamento de Neoplasias , Idoso , PrognósticoRESUMO
BACKGROUND: Information transmission between primary tumor cells and immunocytes or stromal cells in distal organs is a critical factor in the formation of pre-metastatic niche (PMN). Understanding this mechanism is essential for developing effective therapeutic strategy against tumor metastasis. Our study aims to prove the hypothesis that circ-0034880-enriched tumor-derived extracellular vesicles (TEVs) mediate the formation of PMN and colorectal cancer liver metastasis (CRLM), and targeting circ-0034880-enriched TEVs might be an effective therapeutic strategy against PMN formation and CRLM. METHODS: We utilized qPCR and FISH to measure circRNAs expression levels in human CRC plasma, primary CRC tissues, and liver metastatic tissues. Additionally, we employed immunofluorescence, RNA sequencing, and in vivo experiments to assess the effect mechanism of circ-0034880-enriched TEVs on PMN formation and CRC metastasis. DARTS, CETSA and computational docking modeling were applied to explore the pharmacological effects of Ginsenoside Rb1 in impeding PMN formation. RESULTS: We found that circ-0034880 was highly enriched in plasma extracellular vesicles (EVs) derived from CRC patients and closely associated with CRLM. Functionally, circ-0034880-enriched TEVs entered the liver tissues and were absorbed by macrophages in the liver through bloodstream. Mechanically, TEVs-released circ-0034880 enhanced the activation of SPP1highCD206+ pro-tumor macrophages, reshaping the metastasis-supportive host stromal microenvironment and promoting overt metastasis. Importantly, our mechanistic findings led us to discover that the natural product Ginsenoside Rb1 impeded the activation of SPP1highCD206+ pro-tumor macrophages by reducing circ-0034880 biogenesis, thereby suppressing PMN formation and inhibiting CRLM. CONCLUSIONS: Circ-0034880-enriched TEVs facilitate strong interaction between primary tumor cells and SPP1highCD206+ pro-tumor macrophages, promoting PMN formation and CRLM. These findings suggest the potential of using Ginsenoside Rb1 as an alternative therapeutic agent to reshape PMN formation and prevent CRLM.
Assuntos
Neoplasias Colorretais , Vesículas Extracelulares , Neoplasias Hepáticas , Osteopontina , RNA Circular , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Vesículas Extracelulares/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Animais , RNA Circular/genética , Osteopontina/metabolismo , Osteopontina/genética , Linhagem Celular Tumoral , Microambiente Tumoral , Masculino , Feminino , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Postoperative liver metastasis significantly impacts the prognosis of pancreatic neuroendocrine tumor (panNET) patients after R0 resection. Combining computational pathology and deep learning radiomics can enhance the detection of postoperative liver metastasis in panNET patients. METHODS: Clinical data, pathology slides, and radiographic images were collected from 163 panNET patients post-R0 resection at Fudan University Shanghai Cancer Center (FUSCC) and FUSCC Pathology Consultation Center. Digital image analysis and deep learning identified liver metastasis-related features in Ki67-stained whole slide images (WSIs) and enhanced CT scans to create a nomogram. The model's performance was validated in both internal and external test cohorts. RESULTS: Multivariate logistic regression identified nerve infiltration as an independent risk factor for liver metastasis (p < 0.05). The Pathomics score, which was based on a hotspot and the heterogeneous distribution of Ki67 staining, showed improved predictive accuracy for liver metastasis (AUC = 0.799). The deep learning-radiomics (DLR) score achieved an AUC of 0.875. The integrated nomogram, which combines clinical, pathological, and imaging features, demonstrated outstanding performance, with an AUC of 0.985 in the training cohort and 0.961 in the validation cohort. High-risk group had a median recurrence-free survival of 28.5 months compared to 34.7 months for the low-risk group, showing significant correlation with prognosis (p < 0.05). CONCLUSION: A new predictive model that integrates computational pathologic scores and deep learning-radiomics can better predict postoperative liver metastasis in panNET patients, aiding clinicians in developing personalized treatments.
Assuntos
Aprendizado Profundo , Neoplasias Hepáticas , Tumores Neuroendócrinos , Nomogramas , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Tumores Neuroendócrinos/diagnóstico por imagem , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Adulto , Análise Multivariada , Período Pós-Operatório , Prognóstico , Tomografia Computadorizada por Raios X , RadiômicaRESUMO
PURPOSE: Hepatic metastasis frequently occurs in patients who have undergone radical pancreatic resection for pancreatic cancer. Besides chemotherapy, various local treatment approaches targeting hepatic lesions have been explored. However, research on radiofrequency ablation (RFA) as a localized therapy for hepatic metastasis is limited. Therefore, we conducted this retrospective study to provide clinical evidence. METHODS: This is a single-center, retrospective, cohort study. After radical pancreaticoduodenectomy, 32 patients developed metachronous hepatic metastasis with fewer than 3 lesions, the largest of which was less than 3 cm in diameter. These patients underwent combined treatment with chemotherapy and RFA. After 8 weeks of chemotherapy, patients received RFA for hepatic lesions. Additional chemotherapy was administered, and the patients' tumor status and survival were monitored. The primary endpoint of this study was overall survival (OS). Factors affecting OS were analyzed using the Cox risk model. RESULTS: Among the 32 patients, the mean OS was 28.4 months. Univariate and multivariate Cox regression analysis revealed that the time (in months) of liver metastasis (HR = 0.04, 95% CI: 0.01 to 0.19; P < 0.001), the number of liver metastases (HR = 7.08, 95% CI: 1.85 to 27.08, P = 0.004), and PD (progressive disease) response to the second round of chemotherapy (HR = 29.50, 95% CI: 1.46 to 597.27; P = 0.027) were independent predictors of poorer survival. CONCLUSION: Combined therapy with RFA and chemotherapy is safe in patients with hepatic metastasis after radical pancreaticoduodenectomy. Early recurrence (≤12 months), three liver metastatic lesions, and a poor response to the second round of chemotherapy were associated with poor survival.
Assuntos
Neoplasias Hepáticas , Neoplasias Pancreáticas , Ablação por Radiofrequência , Humanos , Masculino , Feminino , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Retrospectivos , Ablação por Radiofrequência/métodos , Idoso , Terapia Combinada , Pancreaticoduodenectomia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , AdultoRESUMO
BACKGROUND: Colorectal cancer is the third most common tumour entity in the world and up to 50% of the patients develop liver metastases (CRLM) within five years. To improve and personalize therapeutic strategies, new diagnostic tools are urgently needed. For instance, biomechanical tumour properties measured by magnetic resonance elastography (MRE) could be implemented as such a diagnostic tool. We postulate that ex vivo MRE combined with histological and radiological evaluation of CRLM could provide biomechanics-based diagnostic markers for cell viability in tumours. METHODS: 34 CRLM specimens from patients who had undergone hepatic resection were studied using ex vivo MRE in a frequency range from 500 Hz to 5300 Hz with increments of 400 Hz. Single frequency evaluation of shear wave speed and wave penetration rate as proxies for stiffness and viscosity was performed, along with rheological model fitting based on the spring-pot model and powerlaw exponent α, ranging between 0 (complete solid behaviour) and 1 (complete fluid behaviour). For histological analysis, samples were stained with H&E and categorized according to the degree of regression. Quantitative histologic analysis was performed to analyse nucleus size, aspect ratio, and density. Radiological response was assessed according to RECIST-criteria. RESULTS: Five samples showed major response to chemotherapy, six samples partial response and 23 samples no response. For higher frequencies (> 2100 Hz), shear wave speed correlated significantly with the degree of regression (p ≤ 0.05) indicating stiffer properties with less viable tumour cells. Correspondingly, rheological analysis of α revealed more elastic-solid tissue properties at low cell viability and major response (α = 0.43 IQR 0.36, 0.47) than at higher cell viability and no response (α = 0.51 IQR 0.48, 0.55; p = 0.03). Quantitative histological analysis showed a decreased nuclear area and density as well as a higher nuclear aspect ratio in patients with major response to treatment compared to patients with no response (all p < 0.05). DISCUSSION: Our results suggest that MRE could be useful in the characterization of biomechanical property changes associated with cell viability in CRLM. In the future, MRE could be applied in clinical diagnosis to support individually tailored therapy plans for patients with CRLM.
Assuntos
Sobrevivência Celular , Neoplasias Colorretais , Técnicas de Imagem por Elasticidade , Elasticidade , Neoplasias Hepáticas , Humanos , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Viscosidade , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
Hepatocellular carcinoma (HCC), sixth most common cancer world-over, commonly metastasizes to lung, lymph nodes and adrenal glands. Incidence of osseous metastases in HCC has been reported to be 3-20 % which occurs predominantly in the axial skeleton. It only rarely occurs in the appendicular skeleton and that too as the solitary focus of metastatic deposit.3,4 We present a case of HCC with solitary osseous metastases to the proximal tibia.
Assuntos
Neoplasias Ósseas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Tíbia , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Ósseas/secundário , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Masculino , Tíbia/diagnóstico por imagem , Tíbia/patologia , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Pessoa de Meia-IdadeRESUMO
Introduction: In recent years, the development of drug-eluting embolization beads that can be imaged has become a hot research topic in regard to meeting clinical needs. In our previous study, we successfully developed nano-assembled microspheres (NAMs) for multimodal imaging purposes. NAMs can not only be visualized under CT/MR/Raman imaging but can also load clinically required doses of doxorubicin. It is important to systematically compare the pharmacokinetics of NAMs with those of commercially available DC Beads and CalliSpheres to evaluate the clinical application potential of NAMs. Methods: In our study, we compared NAMs with two types of drug-eluting beads (DEBs) in terms of irinotecan, drug-loading capacity, release profiles, microsphere diameter variation, and morphological characteristics. Results: Our results indicate that NAMs had an irinotecan loading capacity similar to those of DC Beads and CalliSpheres but exhibited better sustained release in vitro. Conclusion: NAMs have great potential for application in transcatheter arterial chemoembolization for the treatment of colorectal cancer liver metastases.
Assuntos
Irinotecano , Microesferas , Imagem Multimodal , Irinotecano/administração & dosagem , Irinotecano/farmacologia , Humanos , Imagem Multimodal/métodos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Quimioembolização Terapêutica/métodos , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico por imagem , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Camptotecina/farmacologiaRESUMO
Desmosomes are intercellular adhesion complexes providing mechanical coupling and tissue integrity. Previously, a correlation of desmosomal molecule expression with invasion and metastasis formation in several tumor entities was described together with a relevance for circulating tumor cell cluster formation. Here, we investigated the contribution of the desmosomal core adhesion molecule desmoglein-2 (DSG2) to the initial steps of liver metastasis formation by pancreatic cancer cells using a novel ex vivo liver perfusion mouse model. We applied the pancreatic ductal adenocarcinoma cell line AsPC-1 with and without a knockout (KO) of DSG2 and generated mouse lines with a hepatocyte-specific KO of the known interacting partners of DSG2 (DSG2 and desmocollin-2). Liver perfusion with DSG2 KO AsPC-1 cells led to smaller circulating cell clusters and a reduced number of cells adhering to murine livers compared to control cells. While this was independent of the expression levels of desmosomal adhesion molecules in hepatocytes, we show that increased cluster size of cancer cells, which correlates with stronger cell-cell adhesion and expression of desmosomal molecules, is a major factor contributing to the early phase of metastatic spreading. In conclusion, impaired desmosomal adhesion results in reduced circulating cell cluster size, which is relevant for seeding and attachment of metastatic cells to the liver.
Assuntos
Adesão Celular , Desmogleína 2 , Desmossomos , Neoplasias Hepáticas , Neoplasias Pancreáticas , Animais , Desmossomos/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Camundongos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Linhagem Celular Tumoral , Humanos , Desmogleína 2/metabolismo , Desmogleína 2/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Camundongos Knockout , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologiaRESUMO
BACKGROUND: Laparoscopic liver surgery is increasingly used for more challenging procedures. The aim of this study was to assess the feasibility and oncological safety of laparoscopic right hepatectomy for colorectal liver metastases after portal vein embolization. METHODS: This was an international retrospective multicentre study of patients with colorectal liver metastases who underwent open or laparoscopic right and extended right hepatectomy after portal vein embolization between 2004 and 2020. The perioperative and oncological outcomes for patients who underwent laparoscopic and open approaches were compared using propensity score matching. RESULTS: Of 338 patients, 84 patients underwent a laparoscopic procedure and 254 patients underwent an open procedure. Patients in the laparoscopic group less often underwent extended right hepatectomy (18% versus 34.6% (P = 0.004)), procedures in the setting of a two-stage hepatectomy (42% versus 65% (P < 0.001)), and major concurrent procedures (4% versus 16.1% (P = 0.003)). After propensity score matching, 78 patients remained in each group. The laparoscopic approach was associated with longer operating and Pringle times (330 versus 258.5 min (P < 0.001) and 65 versus 30 min (P = 0.001) respectively) and a shorter length of stay (7 versus 8 days (P = 0.011)). The R0 resection rate was not different (71% for the laparoscopic approach versus 60% for the open approach (P = 0.230)). The median disease-free survival was 12 (95% c.i. 10 to 20) months for the laparoscopic approach versus 20 (95% c.i. 13 to 31) months for the open approach (P = 0.145). The median overall survival was 28 (95% c.i. 22 to 48) months for the laparoscopic approach versus 42 (95% c.i. 35 to 52) months for the open approach (P = 0.614). CONCLUSION: The advantages of a laparoscopic over an open approach for (extended) right hepatectomy for colorectal liver metastases after portal vein embolization are limited.
Assuntos
Neoplasias Colorretais , Embolização Terapêutica , Hepatectomia , Laparoscopia , Neoplasias Hepáticas , Veia Porta , Humanos , Hepatectomia/métodos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Colorretais/patologia , Laparoscopia/métodos , Masculino , Feminino , Veia Porta/cirurgia , Embolização Terapêutica/métodos , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Pontuação de Propensão , Resultado do Tratamento , Estudos de Viabilidade , Tempo de InternaçãoRESUMO
Objective: To investigate the differences of protein expressions in the primary tumors, adjacent tissues, and metastatic tumors of gastrointestinal neuroendocrine neoplasms. Methods: Nine patients with gastrointestinal neuroendocrine tumors (GI-NENs) with liver metastasis who underwent surgery at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences from July 2015 to April 2019 were selected. The protein expressions of the primary tissues, liver metastatic tissues, and adjacent tissues were detected by the data independent acquisition (DIA) technology. P<0.05 and | log2FC|>0.5 (FC as the difference multiple) were used as the criteria to identify the differentially expressed proteins in the primary tissues vs adjacent tissues, primary tissues vs liver metastatic tissues, primary tissues with different degrees of differentiation, and liver metastatic tissues with different degrees of differentiation. The differentially expressed proteins were investigated by volcano map analysis, cluster analysis, Gene Ontology (GO) function analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results: Compared with adjacent tissues, 85 proteins were downregulated and 42 proteins were upregulated in the primary tissues of gastric NENs. The differentially expressed proteins were mainly enriched in the biological processes related to the regulation of guanosidase triphosphate activity and the catabolism of deoxyribonucleoside monophosphate, the glycosaminoglycan biosynthesis chondroitin sulfate/dermatan sulfate, pantothenate, and CoA biosynthesis signaling pathways. 114 proteins were downregulated and 155 proteins were upregulated in the primary tissues of intestinal NENs. The differentially expressed proteins were mainly enriched in the biological processes related to glutathione metabolism and sulfur compound metabolism, collecting duct acid secretion, and taurine and hytaurine metabolism signaling pathways. Compared with the primary tissues of neuroendocrine cancers (NECs), 168 proteins were downregulated and 278 proteins were upregulated in G1-2 differentiation primary tissues. The differentially expressed proteins were significantly enriched in biological processes such as DNA metabolism and DNA replication, as well as replication, mismatch repair, and other pathways. Compared with the metastatic tissues of NECs, 95 proteins were downregulated and 97 proteins were upregulated in G1-2 differentiated metastases. The differentially expressed proteins were significantly enriched in the activity and catalytic activity of transcriptional coactivators, base excision repair, and protein efflux pathways. Compared with G1 differentiated primary tissues, 530 proteins were downregulated and 211 proteins were upregulated in G1 differentiated metastatic tissues. Compared with G2 differentiated primary lesions, 53 proteins were downregulated and 96 proteins were upregulated in G2 differentiated metastatic tissues. Compared with the primary lesions of NECs, 109 proteins were downregulated and 92 proteins were upregulated in the metastatic tissues of NECs. In G1 and G2 differentiated GI-NENs, there are many similar signal pathways enriched in differentially expressed proteins between primary lesions and metastases, while only one signal pathway enriched in differentially expressed proteins between primary and metastatic tissues of NECs is the same as that enriched in differentially expressed proteins between primary and metastatic tissues of GI-NENs, which is the drug metabolism signal pathway. The differentially expressed proteins in G1 differentiated primary and metastatic tissues were mainly expressed in cytoplasm (20.26%), mitochondria (18.67%), and nucleus (15.48%). The differentially expressed proteins in the primary and metastatic tissues of G2 differentiation were mainly expressed in the cytoplasm (20.24%), nucleus (18.25%), and cell membrane (15.08%). The differentially expressed proteins in the primary and metastatic tissues of NECs were mainly expressed in the nucleus (23.78%), cytoplasm (22.7%), and cell membrane (11.35%). Conclusion: The protein expressions of GI-NENs in the primary tissues, adjacent tissues, and metastatic tissues were significantly different in different sites and degrees of differentiation.
Assuntos
Neoplasias Gastrointestinais , Neoplasias Hepáticas , Tumores Neuroendócrinos , Proteômica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Proteoma/metabolismoRESUMO
Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS- tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS- tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.
Assuntos
Quimiocina CCL19 , Neoplasias Colorretais , Imunoglobulina G , Neoplasias Hepáticas , Estruturas Linfoides Terciárias , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Animais , Estruturas Linfoides Terciárias/imunologia , Estruturas Linfoides Terciárias/patologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Camundongos , Imunoglobulina G/imunologia , Quimiocina CCL19/metabolismo , Quimiocina CCL19/genética , Fibroblastos/metabolismo , Fibroblastos/imunologia , Anticorpos Monoclonais/farmacologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Feminino , Linhagem Celular TumoralRESUMO
BACKGROUND: The liver is affected by two groups of malignant tumours: primary liver cancers and liver metastases. Liver metastases are significantly more common than primary liver cancer, and five-year survival after radical surgical treatment of liver metastases ranges from 28% to 50%, depending on primary cancer site. However, R0 resection (resection for cure) is not feasible in most people; therefore, other treatments have to be considered in the case of non-resectability. One possible option is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Transarterial chemoembolisation (TACE) of the peripheral branches of the hepatic artery can be achieved by administering a chemotherapeutic drug followed by vascular occlusive agents and can lead to selective necrosis of the cancer tissue while leaving normal liver parenchyma virtually unaffected. The entire procedure can be performed without infusion of chemotherapy and is then called bland transarterial embolisation (TAE). These procedures are usually applied over a few sessions. Another possible treatment option is systemic chemotherapy which, in the case of colorectal cancer metastases, is most commonly performed using FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) regimens applied in multiple sessions over a long period of time. These therapies disrupt the cell cycle, leading to death of rapidly dividing malignant cells. Current guidelines determine the role of TAE and TACE as non-curative treatment options applicable in people with liver-only or liver-dominant metastatic disease that is unresectable or non-ablatable, and in people who have failed systemic chemotherapy. Regarding the treatment modalities in people with colorectal cancer liver metastases, we found no systematic reviews comparing the efficacy of TAE or TACE versus systemic chemotherapy. OBJECTIVES: To evaluate the beneficial and harmful effects of transarterial embolisation (TAE) or transarterial chemoembolisation (TACE) compared with systemic chemotherapy in people with liver-dominant unresectable colorectal cancer liver metastases. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three additional databases up to 4 April 2024. We also searched two trials registers and the European Medicines Agency database and checked reference lists of retrieved publications. SELECTION CRITERIA: We included randomised clinical trials assessing beneficial and harmful effects of TAE or TACE versus systemic chemotherapy in adults (aged 18 years or older) with colorectal cancer liver metastases. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were all-cause mortality; overall survival (time to mortality); and any adverse events or complications. Our secondary outcomes were cancer mortality; health-related quality of life; progression-free survival; proportion of participants dying or surviving with progression of the disease; time to progression of liver metastases; recurrence of liver metastases; and tumour response measures (complete response, partial response, stable disease, and progressive disease). For the purpose of the review and to perform necessary analyses, whenever possible, we converted survival rates to mortality rates, as this was our primary outcome. For the analysis of dichotomous outcomes, we used the risk ratio (RR); for continuous outcomes, we used the mean difference; and for time to event outcomes, we calculated hazard ratios (HRs), all with 95% confidence intervals (CI). We used the standardised mean difference with 95% CIs when the trials used different instruments. We used GRADE to assess the certainty of evidence for each outcome. We based our conclusions on outcomes analysed at the longest follow-up. MAIN RESULTS: We included three trials with 118 participants randomised to TACE versus 120 participants to systemic chemotherapy. Four participants were excluded; one due to disease progression prior to treatment and three due to decline in health. The trials reported data on one or more outcomes. Two trials were performed in China and one in Italy. The trials differed in terms of embolisation techniques and chemotherapeutic agents. Follow-up ranged from 12 months to 50 months. TACE may reduce mortality at longest follow-up (RR 0.86, 95% CI 0.79 to 0.94; 3 trials, 234 participants; very low-certainty evidence), but the evidence is very uncertain. TACE may have little to no effect on overall survival (time to mortality) (HR 0.61, 95% CI 0.37 to 1.01; 1 trial, 70 participants; very low-certainty evidence), any adverse events or complications (3 trials, 234 participants; very low-certainty evidence), health-related quality of life (2 trials, 154 participants; very low-certainty evidence), progression-free survival (1 trial, 70 participants; very low-certainty evidence), and tumour response measures (presented as the overall response rate) (RR 1.81, 95% CI 1.11 to 2.96; 3 trials, 234 participants; very low-certainty evidence), but the evidence is very uncertain. No trials reported cancer mortality, proportion of participants dying or surviving with progression of the disease, and recurrence of liver metastases. We found no trials comparing the effects of TAE versus systemic chemotherapy in people with colorectal cancer liver metastases. AUTHORS' CONCLUSIONS: The evidence regarding effectiveness of TACE versus systemic chemotherapy in people with colorectal cancer liver metastases is of very low certainty and is based on three trials. Our confidence in the results is limited due to the risk of bias, inconsistency, indirectness, and imprecision. It is very uncertain whether TACE confers benefits with regard to reduction in mortality, overall survival (time to mortality), reduction in adverse events or complications, improvement in health-related quality of life, improvement in progression-free survival, and tumour response measures (presented as the overall response rate). Data on cancer mortality, proportion of participants dying or surviving with progression of the disease, and recurrence of liver metastases are lacking. We found no trials assessing TAE versus systemic chemotherapy. More randomised clinical trials are needed to strengthen the body of evidence and provide insight into the benefits and harms of TACE or TAE in comparison with systemic chemotherapy in people with liver metastases from colorectal cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Quimioembolização Terapêutica , Neoplasias Colorretais , Fluoruracila , Leucovorina , Neoplasias Hepáticas , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Quimioembolização Terapêutica/métodos , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Artéria Hepática , Compostos Organoplatínicos/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagemRESUMO
INTRODUCTION: Survival comparisons among patients with liver metastases from pancreatic and rectal neuroendocrine tumors (NETs) were limited, and the efficacy of observation rules in patients undergoing hepatectomy for neuroendocrine liver metastases (NELMs) was unknown. This study aims to distinguish these characteristics and clarify the effects of the observation rules on NELMs. METHODS: Clinical data were separately collected from patients with pancreatic and rectal NELMs at medical centers in both Japan and China. The Japanese cohort followed the observation rules for the resection of NELMs. A comparative analysis was conducted on clinical characteristics and prognosis features such as overall survival time (OS) and disease-free survival interval (DFS-I). RESULTS: Enrollment included 47 and 34 patients from Japan and China, respectively. Of these, 69 and 12 patients had tumors originating from the pancreas and rectum, respectively. The OS time in patients undergoing primary tumor resection was significantly longer; however, the OS time between the patients undergoing and not undergoing radical resection of liver metastasis was the same. In asynchronous NELMs, patients with rectal (R)-NELMs showed a significantly higher proportion of type III NELMs. Additionally, the median DFS-I of asynchronous R-NELMs was longer than the recommended follow-up time, with 71.4% of them classified as G2. In the Japanese cohort, patients who adhered to the observation rules exhibited a longer median DFS after hepatectomy for NELMs compared with their counterparts. CONCLUSION: Although curative surgery is crucial for primary lesions, personalized approaches are required to manage NELMs. Extended overall follow-ups and shortened follow-up intervals are recommended for G2 stage rectal NETs. The observation rules for NELMs require further validation with a larger sample size.
Assuntos
Hepatectomia , Neoplasias Hepáticas , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias Retais , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Masculino , Feminino , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Neoplasias Retais/mortalidade , Pessoa de Meia-Idade , Tumores Neuroendócrinos/cirurgia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/mortalidade , Hepatectomia/mortalidade , Hepatectomia/métodos , Taxa de Sobrevida , Prognóstico , Idoso , Seguimentos , Japão/epidemiologia , Adulto , China/epidemiologia , Estudos RetrospectivosRESUMO
ABSTRACT: Metastatic insulinomas can cause recurrent hypoglycemia requiring continuous IV glucose infusion. Various medical and chemotherapeutic treatment options are used to reduce the patient's risk of death due to hypoglycemia. Treatment-resistant hepatic metastatic insulinomas may benefit clinically from 90Y transarterial radioembolization therapy. In this case, we present a case of liver metastatic insulinoma that achieved clinical improvement after 2 cycles of 90Y microspheres transarterial radioembolization, and the presence of active metastases was demonstrated with 68Ga-NODAGA-exendin-4 PET/CT imaging.
Assuntos
Embolização Terapêutica , Exenatida , Radioisótopos de Gálio , Hipoglicemia , Insulinoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de Ítrio , Humanos , Insulinoma/diagnóstico por imagem , Radioisótopos de Ítrio/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Acetatos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/radioterapia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/radioterapia , Masculino , Metástase Neoplásica , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Uveal melanoma (UM), the most common adult intraocular tumor, is characterized by high malignancy and poor prognosis in advanced stages. Angiogenesis is critical for UM development, however, not only the role of vascular endothelial dysfunction in UM remains unknown, but also their analysis at the single-cell level has been lacking. A comprehensive analysis is essential to clarify the role of the endothelium in the development of UM. METHODS: By using single-cell RNA transcriptomics data of 11 cases of primary and liver metastasis UM, we analyzed the endothelial cell status. In addition, we analyzed and validated ECs in the in vitro model and collected clinical specimens. Subsequently, we explored the impact of endothelial dysfunction on UM cell migration and explored the mechanisms responsible for the endothelial cell abnormalities and the reasons for their peripheral effects. RESULTS: UM metastasis has a significantly higher percentage of vascular endothelial cells compared to in situ tumors, and endothelial cells in metastasis show significant senescence. Senescent endothelial cells in metastatic tumors showed significant Krüppel-like factor 4 (KLF4) upregulation, overexpression of KLF4 in normal endothelial cells induced senescence, and knockdown of KLF4 in senescent endothelium inhibited senescence, suggesting that KLF4 is a driver gene for endothelial senescence. KLF4-induced endothelial senescence drove tumor cell migration through a senescence-associated secretory phenotype (SASP), of which the most important component of the effector was CXCL12 (C-X-C motif chemokine ligand 12), and participated in the composition of the immunosuppressive microenvironment. CONCLUSION: This study provides an undesirable insight of senescent endothelial cells in promoting UM metastasis.
Assuntos
Movimento Celular , Senescência Celular , Células Endoteliais , Fator 4 Semelhante a Kruppel , Neoplasias Hepáticas , Melanoma , Análise de Célula Única , Neoplasias Uveais , Humanos , Neoplasias Uveais/patologia , Neoplasias Uveais/genética , Melanoma/patologia , Melanoma/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Linhagem Celular Tumoral , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/genética , Regulação Neoplásica da Expressão Gênica , Feminino , MasculinoRESUMO
BACKGROUND: Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. METHODS: Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. RESULTS: Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-ß-muricholic acid (Tß-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. CONCLUSIONS: Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism.
Assuntos
Colestase , Neoplasias Colorretais , Neoplasias Hepáticas , Neutrófilos , Animais , Neutrófilos/imunologia , Camundongos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Colestase/imunologia , Colestase/metabolismo , Microambiente Tumoral , Masculino , Camundongos Endogâmicos C57BL , Humanos , Modelos Animais de DoençasRESUMO
Fibrinogen-like protein 1 (FGL1) contributes to the proliferation and metabolism of hepatocytes; however, as a major ligand of the immune checkpoint, its role in the liver regional immune microenvironment is poorly understood. Hepatocytes specifically and highly expressed FGL1 under normal physiological conditions. Increases in hepatic CD8+ T and NK cell numbers and functions were found in Fgl1-deficient (Fgl1-/-) mice, but not in the spleen or lymph node, similar to findings in anti-FGL1 mAb-treated wild-type mice. Furthermore, Fgl1 deficiency or anti-FGL1 mAb blockade restrained liver metastasis and slowed the growth of orthotopic tumors, with significantly prolonged survival of tumor-bearing mice. Tumor-infiltrating hepatic CD8+ T and NK cells upregulated the expression of lymphocyte activation gene-3 (LAG-3) and exhibited stronger antitumor activities after anti-FGL1 treatment. The antitumor efficacy of FGL1 blockade depended on cytotoxic T lymphocytes and NK cells, demonstrated by using a cell-deficient mouse model and cell transfer in vivo. In vitro, FGL1 directly inhibited hepatic T and NK cells related to the receptor LAG-3. In conclusion, hepatocyte-derived FGL1 played critical immunoregulatory roles in the liver and contributed to liver metastasis and tumor growth by inhibiting CD8+ T and NK cell functions via the receptor LAG-3, providing a new strategy for liver cancer immunotherapy.
Assuntos
Linfócitos T CD8-Positivos , Fibrinogênio , Hepatócitos , Células Matadoras Naturais , Neoplasias Hepáticas , Animais , Células Matadoras Naturais/imunologia , Camundongos , Linfócitos T CD8-Positivos/imunologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Fibrinogênio/metabolismo , Camundongos Knockout , Humanos , Microambiente Tumoral/imunologia , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Proteína do Gene 3 de Ativação de Linfócitos , MasculinoRESUMO
Malignant peripheral nerve sheath tumors are frequently associated with neurofibromatosis type 1. They are usually located in the extremities or in the axial area. Its visceral location is very rare and its hepatic origin is infrequent. They tend to be aggressive with a poor response to chemotherapy and radiotherapy, so surgical management is the best treatment option. We present the case of a young man with neurofibromatosis type 1, who presented with hemoperitoneum as a complication of a malignant tumor of the peripheral nerve sheath located in the liver.