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American Journal of Therapeutics 2016The understanding of aberrant molecular pathways that result in gastrointestinal stromal tumors (GISTs) and the rapid development of molecular therapies that target... (Review)
Review
The understanding of aberrant molecular pathways that result in gastrointestinal stromal tumors (GISTs) and the rapid development of molecular therapies that target these pathways represent one of the great milestones in translational oncology. The story of GIST is unique in that targeted molecular therapy was successfully applied in clinical therapeutics, with dramatic results redefining the management of these traditionally chemotherapy-resistant tumors. We briefly review the molecular biology and clinical presentation of GIST and then discuss the adjuvant and neoadjuvant use of tyrosine kinase inhibitors in early-stage GIST and their use in metastatic disease. Newer therapeutic advances in the rapidly changing field of GIST management are also discussed.
Topics: Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Metastasis; Prognosis; Protein-Tyrosine Kinases
PubMed: 23942136
DOI: 10.1097/MJT.0b013e3182a1be76 -
Journal of Zhejiang University.... May 2017The tumor microenvironment (TME) plays an important role in supporting cancer progression. The TME is composed of tumor cells, the surrounding tumor-associated stromal... (Review)
Review
The tumor microenvironment (TME) plays an important role in supporting cancer progression. The TME is composed of tumor cells, the surrounding tumor-associated stromal cells, and the extracellular matrix (ECM). Crosstalk between the TME components contributes to tumorigenesis. Recently, one of our studies showed that pancreatic ductal adenocarcinoma (PDAC) cells can induce DNA methylation in cancer-associated fibroblasts (CAFs), thereby modifying tumor-stromal interactions in the TME, and subsequently creating a TME that supports tumor growth. Here we summarize recent studies about how DNA methylation affects tumorigenesis through regulating tumor-associated stromal components including fibroblasts and immune cells. We also discuss the potential for targeting DNA methylation for the treatment of cancers.
Topics: Animals; Carcinogenesis; DNA Methylation; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Models, Genetic; Neoplasms; Tumor Microenvironment
PubMed: 28471108
DOI: 10.1631/jzus.B1600579 -
Cancer Science Oct 2018Exosomes are representative extracellular vesicles (EV) derived from multivesicular endosomes (MVE) and have been described as new particles in the communication of... (Review)
Review
Exosomes are representative extracellular vesicles (EV) derived from multivesicular endosomes (MVE) and have been described as new particles in the communication of neighborhood and/or distant cells by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and nucleotides including micro (mi) RNAs. Exosomes from immune cells and tumor cells act in part as a regulator in tumor immunology. CD8 T cells that show potent cytotoxic activity against tumor cells reside as an inactive naïve form in the T-cell zone of secondary lymphoid organs. Once receiving tumor-specific antigenic stimulation by dendritic cells (DC), CD8 T cells are activated and differentiated into effector CTL. Subsequently, CTL circulate systemically, infiltrate into tumor lesions through the stromal neovasculature where mesenchymal stromal cells, for example, mesenchymal stem cells (MSC) and cancer-associated fibroblasts (CAF), abundantly exist, destroy mesenchymal tumor stroma in an exosome-mediated way, go into tumor parenchyma, and attack tumor cells by specific interaction. DC-derived and regulatory T (Treg) cell-derived exosomes, respectively, promote and inhibit CTL generation in this setting. In this review, we describe the roles of exosomes from immune cells and tumor cells on the regulation of tumor progression.
Topics: Antigens, Neoplasm; Cytotoxicity, Immunologic; Disease Progression; Exosomes; Humans; Immunity, Cellular; Neoplasm Invasiveness; Neoplasms; Signal Transduction
PubMed: 29999574
DOI: 10.1111/cas.13735 -
Applied Immunohistochemistry &... Sep 2021Programmed death-1 (PD1) expression has not been reported in gallbladder adenocarcinoma. In this study we examined PD1 expression in gallbladder cancer to explore the...
Programmed death-1 (PD1) expression has not been reported in gallbladder adenocarcinoma. In this study we examined PD1 expression in gallbladder cancer to explore the correlation between PD1 expression and the clinicopathologic parameters. We found that 98% (46/47) cases expressed programmed death-ligand 1 (PD-L1) with 85% cases being PD-L1 3+. PD1+ tumor-infiltrating lymphocytes (TILs) were present in 78.7% cases (37/47). The tumor size was significantly smaller and the stromal CD3+ TILs were significantly higher in tumors with PD1+ TILs than those with PD1- TILs. In the tumors with size of <3 cm, stromal CD3+ TILs >115/HPF or stromal CD8+ TILs >45/HPF were associated with much better survival than those with stromal CD3+ TILs ≤115/HPF or stromal CD8+ TILs ≤45/HPF. In tumors with the size of 3 cm or larger, PD1+ TILs or stromal CD8+ TILs >45/HPF carried a significantly poorer survival than PD1- tumors or stromal CD8+ TILs <=45/HPF. No correlation was identified between PD1 expression and lymphovascular invasion, distant metastasis, pathologic tumor stage or prognostic stage. Multivariate survival analysis showed that tumor TNM stage and age were independent prognostic factors in gallbladder adenocarcinomas. We conclude that gallbladder adenocarcinomas may have high PD-L1 expression and PD1+ TILs. Smaller tumor size and greater amount of stromal CD3+ T cells were found in tumors with PD1+ TILs. In small tumors (<3 cm), high stromal CD3+ TILs or high stromal CD8+ TILs were associated with better survival. However, in large tumors (≥3 cm), PD1+ TILs or high stromal CD8+ TILs carried a poorer survival. Our study implied that immune-based therapy including PD1/PD-L1 checkpoint blockade might be useful in gallbladder adenocarcinomas.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Female; Gallbladder Neoplasms; Humans; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Retrospective Studies; Tumor Microenvironment
PubMed: 33710123
DOI: 10.1097/PAI.0000000000000922 -
Annals of Diagnostic Pathology Apr 2019Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal lesions of the gastrointestinal tract. A small minority of GISTs exhibit morphologic and... (Review)
Review
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal lesions of the gastrointestinal tract. A small minority of GISTs exhibit morphologic and phenotypic changes and differentiate into an unusual phenotype through the process of dedifferentiation. Dedifferentiation can occur either de novo or after prolonged treatment with imatinib, a selective tyrosine kinase inhibitor. GISTs can present with various morphologies including rhabdomyosarcoma, angiosarcoma, or undifferentiated pleomorphic sarcoma. The unusual histologic and immunohistochemical characteristics of these tumors can be diagnostically challenging. Therefore, it is essential that the pathologists recognize GISTs with unusual morphology and be aware of the dedifferentiation process. This review aims to provide an overview of the morphologic and molecular features of dedifferentiated GISTs. Additionally, we discuss diagnostic dilemmas and recent immunohistochemical markers that are useful in distinguishing dedifferentiated GISTs from other gastrointestinal tumors.
Topics: Biomarkers, Tumor; Cell Dedifferentiation; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Immunohistochemistry
PubMed: 30661742
DOI: 10.1016/j.anndiagpath.2018.12.005 -
Advances in Experimental Medicine and... 2018The tumor microenvironment comprises a mass of heterogeneous cell types, including immune cells, endothelial cells, and fibroblasts, alongside cancer cells. It is... (Review)
Review
The tumor microenvironment comprises a mass of heterogeneous cell types, including immune cells, endothelial cells, and fibroblasts, alongside cancer cells. It is increasingly becoming clear that the development of this support niche is critical to the continued uncontrolled growth of the cancer. The tumor microenvironment contributes to the maintenance of cancer stemness and also directly promotes angiogenesis, invasion, metastasis, and chronic inflammation. In this chapter, we describe on the role of fibroblasts, specifically termed cancer-associated fibroblasts (CAFs), in the promotion and maintenance of cancers. CAFs have a multitude of effects on the growth and maintenance of cancer, and here we focus on their roles in modulating immune cells and responses; CAFs both inhibit immune cell access to the tumor microenvironment and inhibit their functions within the tumor. Finally, we describe the potential modulation of CAF function as an adjunct to bolster the effectiveness of cancer immunotherapies.
Topics: Animals; Drug Resistance, Neoplasm; Humans; Neoplasms; Neovascularization, Pathologic; Stromal Cells; Tumor Microenvironment
PubMed: 30155624
DOI: 10.1007/978-3-319-78127-3_6 -
British Journal of Cancer Jan 2021Although substantial progress has been made over the past 40 years in treating patients with cancer, effective therapies for those who are diagnosed with advanced... (Review)
Review
Although substantial progress has been made over the past 40 years in treating patients with cancer, effective therapies for those who are diagnosed with advanced metastatic disease are still few and far between. Cancer cells do not exist in isolation: rather, they exist within a complex microenvironment composed of stromal cells and extracellular matrix. Within this tumour microenvironment exists an interplay between the two main stromal cell subtypes, cancer-associated fibroblasts (CAFs) and immune cells, that are important in controlling metastasis. A complex network of paracrine signalling pathways between CAFs, immune cells and tumour cells are involved at multiple stages of the metastatic process, from invasion and intravasation at the primary tumour site to extravasation and colonisation in the metastatic site. Heterogeneity and plasticity within stromal cell populations also contribute to the complexity. Although many of these processes are likely to be common to a number of metastatic sites, we will describe in detail the interplay within the liver, a preferred site of metastasis for many tumours. A greater understanding of these networks provides opportunities for the design of new therapeutic approaches for targeting the metastatic disease.
Topics: Animals; Cancer-Associated Fibroblasts; Fibrosis; Humans; Liver; Neoplasm Invasiveness; Neoplasms; Tumor Microenvironment
PubMed: 33239677
DOI: 10.1038/s41416-020-01172-1 -
Oncology Research and Treatment 2018Like other uterine sarcomas, low-grade endometrial stromal sarcomas (LG-ESS) are a very rare tumor entity. In the past, research studies therefore discussed the various... (Review)
Review
Like other uterine sarcomas, low-grade endometrial stromal sarcomas (LG-ESS) are a very rare tumor entity. In the past, research studies therefore discussed the various different types of the disease in combination. In addition, the classification of endometrial stromal tumors presented difficulties for quite some time so that in earlier studies it was not always possible to precisely distinguish between LG-ESS, high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. For LG-ESS, surgery with hysterectomy and adnexectomy is the first-line treatment. The benefits of lymphadenectomy and tumor debulking are unclear. Endocrine therapy with gestagens and aromatase inhibitors is under discussion to provide adjuvant treatment for patients with advanced stages of the disease. As radiotherapy only provides locoregional control, and in view of the usually good prognosis of patients with LG-ESS, its benefits need to be weighed against its side effects. In the case of recurrence, repeat surgery is the first choice. Further research studies viewing LG-ESS as a distinct entity are needed in order to improve treatment options for patients with LG-ESS.
Topics: Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Endometrial Neoplasms; Endometrium; Female; Humans; Hysterectomy; Lymph Node Excision; Neoplasm Grading; Neoplasm Recurrence, Local; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Reoperation; Salpingo-oophorectomy; Sarcoma, Endometrial Stromal
PubMed: 30317238
DOI: 10.1159/000494225 -
Current Opinion in Clinical Nutrition... Jul 2017Lipid metabolism in cancer cells and tumor-associated stromal cells was recently identified to contribute to disease progression particularly in response to changes in... (Review)
Review
PURPOSE OF REVIEW
Lipid metabolism in cancer cells and tumor-associated stromal cells was recently identified to contribute to disease progression particularly in response to changes in tumor microenvironment such as acidosis and hypoxia.
RECENT FINDINGS
New molecular mechanisms driving lipid metabolism in various cancers were elicited through genetic silencing, pharmacological inhibition of key metabolic enzymes, including those involved in fatty acid oxidation and synthesis, and modulation of diet composition.
SUMMARY
To proliferate, metastasize, or resist stress conditions imposed by the microenvironment, many cancer cells rely on fatty acid β-oxidation to generate acetyl-CoA and fuel the TCA cycle, and on fatty acid synthesis to produce building blocks. These processes are fine-tuned through regulation of acetyl-CoA carboxylases expression and activity. Stromal cells including lymphocytes, (lymphatic) endothelial cells and adipocytes also participate through either fatty acid transfer or lipid-based signaling to cancer disease progression. Altogether, these data identify critical nodes in the orchestration of lipid metabolism in cancer that may facilitate the design of synthetic-lethal treatments.
Topics: Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Animals; Citric Acid Cycle; Drug Resistance, Neoplasm; Fatty Acids; Humans; Lipid Metabolism; Neoplasm Metastasis; Neoplasms; Obesity; Oxidation-Reduction; Stromal Cells
PubMed: 28403011
DOI: 10.1097/MCO.0000000000000381 -
Mayo Clinic Proceedings Feb 2019
Topics: Biopsy; DNA Mutational Analysis; DNA, Neoplasm; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Mutation; Proto-Oncogene Proteins c-kit
PubMed: 30711139
DOI: 10.1016/j.mayocp.2018.12.019