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International Journal of Molecular... Apr 2019Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and lacks effective therapeutic approaches. Most HCC develops in the setting of chronic... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and lacks effective therapeutic approaches. Most HCC develops in the setting of chronic liver injury, hepatic inflammation, and fibrosis. Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) are key players in liver fibrogenesis and hepatocarcinogenesis, respectively. CAFs, which probably derive from HSCs, activate into extracellular matrix (ECM)-producing myofibroblasts and crosstalk with cancer cells to affect tumor growth and invasion. In this review, we describe the different components which form the HCC premalignant microenvironment (PME) and the tumor microenvironment (TME), focusing on the liver fibrosis process and the biology of CAFs. We will describe the CAF-dependent mechanisms which have been suggested to promote hepatocarcinogenesis, such as the alteration of ECM, CAF-dependent production of cytokines and angiogenic factors, CAF-dependent reduction of immuno-surveillance, and CAF-dependent promotion of epithelial-mesenchymal transition (EMT). New knowledge of the fibrosis process and the role of CAFs in HCC may pave the way for new therapeutic strategies for liver cancer.
Topics: Animals; Carcinoma, Hepatocellular; Fibroblasts; Fibrosis; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Liver Neoplasms; Tumor Microenvironment
PubMed: 30959975
DOI: 10.3390/ijms20071723 -
The British Journal of Radiology Feb 2022Brenner tumors are rare ovarian neoplasms composed of ovarian transition cells surrounded by dense fibrous tissue. Most of them are small tumors (<2 cm), detected...
Brenner tumors are rare ovarian neoplasms composed of ovarian transition cells surrounded by dense fibrous tissue. Most of them are small tumors (<2 cm), detected incidentally in asymptomatic women. Its predominantly fibrous content results in relatively low signal on weighted images, establishing differential diagnosis with ovarian fibroma and thecoma. Their imaging features are very similar, the differentiation is based on secondary characteristics, such as signs or symptoms of estrogen excess and the presence of a second ovarian neoplasm, which has been reported in up to 30% of patients with Brenner tumor. Although originally thought to be universally benign, there have been scattered reports in the past decades of borderline and malignant forms of Brenner tumors.
Topics: Brenner Tumor; Cystadenofibroma; Diagnosis, Differential; Female; Fibroma; Humans; Leiomyoma; Magnetic Resonance Imaging; Ovarian Neoplasms; Rare Diseases; Thecoma; Tomography, X-Ray Computed; Ultrasonography
PubMed: 34928171
DOI: 10.1259/bjr.20210687 -
Cell Metabolism May 2020Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic...
Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine's functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.
Topics: Animals; Glutathione; Mice; Serine; T-Lymphocytes, Regulatory
PubMed: 32213345
DOI: 10.1016/j.cmet.2020.03.004 -
Physiological Reviews Jan 2019The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies (TNFSF/TNFRSF) include 19 ligands and 29 receptors that play important roles in the modulation of... (Review)
Review
The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies (TNFSF/TNFRSF) include 19 ligands and 29 receptors that play important roles in the modulation of cellular functions. The communication pathways mediated by TNFSF/TNFRSF are essential for numerous developmental, homeostatic, and stimulus-responsive processes in vivo. TNFSF/TNFRSF members regulate cellular differentiation, survival, and programmed death, but their most critical functions pertain to the immune system. Both innate and adaptive immune cells are controlled by TNFSF/TNFRSF members in a manner that is crucial for the coordination of various mechanisms driving either co-stimulation or co-inhibition of the immune response. Dysregulation of these same signaling pathways has been implicated in inflammatory and autoimmune diseases, highlighting the importance of their tight regulation. Investigation of the control of TNFSF/TNFRSF activities has led to the development of therapeutics with the potential to reduce chronic inflammation or promote anti-tumor immunity. The study of TNFSF/TNFRSF proteins has exploded over the last 30 yr, but there remains a need to better understand the fundamental mechanisms underlying the molecular pathways they mediate to design more effective anti-inflammatory and anti-cancer therapies.
Topics: Animals; Autoimmune Diseases; Humans; Immune System; Inflammation; Ligands; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factors
PubMed: 30354964
DOI: 10.1152/physrev.00045.2017 -
British Journal of Cancer Oct 2018Colorectal cancer (CRC) is both one of the most common and one of the most preventable cancers globally, with powerful but strongly missed potential for primary,... (Review)
Review
Colorectal cancer (CRC) is both one of the most common and one of the most preventable cancers globally, with powerful but strongly missed potential for primary, secondary and tertiary prevention. CRC incidence has traditionally been the highest in affluent Western countries, but it is now increasing rapidly with economic development in many other parts of the world. CRC shares several main risk factors, such as smoking, excessive alcohol consumption, physical inactivity and being overweight, with other common diseases; therefore, primary prevention efforts to reduce these risk factors are expected to have multiple beneficial effects that extend beyond CRC prevention, and should have high public health impact. A sizeable reduction in the incidence and mortality of CRC can also be achieved by offering effective screening tests, such as faecal immunochemical tests, flexible sigmoidoscopy and colonoscopy, in organised screening programmes which have been implemented in an increasing number of countries. Countries with early and high uptake rates of effective screening have exhibited major declines in CRC incidence and mortality, in contrast to most other countries. Finally, increasing evidence shows that the prognosis and quality of life of CRC patients can be substantially improved by tertiary prevention measures, such as the administration of low-dose aspirin and the promotion of physical activity.
Topics: Colorectal Neoplasms; Early Detection of Cancer; Epidemics; Healthy Lifestyle; Humans; Incidence; Primary Prevention; Prognosis; Risk Assessment; Secondary Prevention; Tertiary Prevention
PubMed: 30287914
DOI: 10.1038/s41416-018-0264-x -
The American Journal of Surgical... Mar 2010Ovarian cancer is the most lethal gynecologic malignancy. Efforts at early detection and new therapeutic approaches to reduce mortality have been largely unsuccessful,...
Ovarian cancer is the most lethal gynecologic malignancy. Efforts at early detection and new therapeutic approaches to reduce mortality have been largely unsuccessful, because the origin and pathogenesis of epithelial ovarian cancer are poorly understood. Despite numerous studies that have carefully scrutinized the ovaries for precursor lesions, none have been found. This has led to the proposal that ovarian cancer develops de novo. Studies have shown that epithelial ovarian cancer is not a single disease but is composed of a diverse group of tumors that can be classified based on distinctive morphologic and molecular genetic features. One group of tumors, designated type I, is composed of low-grade serous, low-grade endometrioid, clear cell, mucinous and transitional (Brenner) carcinomas. These tumors generally behave in an indolent fashion, are confined to the ovary at presentation and, as a group, are relatively genetically stable. They lack mutations of TP53, but each histologic type exhibits a distinctive molecular genetic profile. Moreover, the carcinomas exhibit a shared lineage with the corresponding benign cystic neoplasm, often through an intermediate (borderline tumor) step, supporting the morphologic continuum of tumor progression. In contrast, another group of tumors, designated type II, is highly aggressive, evolves rapidly and almost always presents in advanced stage. Type II tumors include conventional high-grade serous carcinoma, undifferentiated carcinoma, and malignant mixed mesodermal tumors (carcinosarcoma). They displayTP53 mutations in over 80% of cases and rarely harbor the mutations that are found in the type I tumors. Recent studies have also provided cogent evidence that what have been traditionally thought to be primary ovarian tumors actually originate in other pelvic organs and involve the ovary secondarily. Thus, it has been proposed that serous tumors arise from the implantation of epithelium (benign or malignant) from the fallopian tube. Endometrioid and clear cell tumors have been associated with endometriosis that is regarded as the precursor of these tumors. As it is generally accepted that endometriosis develops from endometrial tissue by retrograde menstruation, it is reasonable to assume that the endometrium is the source of these ovarian neoplasms. Finally, preliminary data suggest that mucinous and transitional (Brenner) tumors arise from transitional-type epithelial nests at the tubal-mesothelial junction by a process of metaplasia. Appreciation of these new concepts will allow for a more rationale approach to screening, treatment, and prevention that potentially can have a significant impact on reducing the mortality of this devastating disease.
Topics: Animals; Biomarkers, Tumor; Cell Transformation, Neoplastic; Disease Progression; Early Detection of Cancer; Endometrium; Epithelial Cells; Fallopian Tubes; Female; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Metaplasia; Neoplasm Invasiveness; Neoplasm Staging; Ovarian Neoplasms; Ovary; Risk Factors
PubMed: 20154587
DOI: 10.1097/PAS.0b013e3181cf3d79 -
Archives of Pathology & Laboratory... Oct 2019Brenner tumors arise from ovarian epithelium, accounting for approximately 5% of benign ovarian epithelial tumors. The World Health Organization classification groups... (Review)
Review
Brenner tumors arise from ovarian epithelium, accounting for approximately 5% of benign ovarian epithelial tumors. The World Health Organization classification groups them into benign, borderline, and malignant on the basis of proliferation and invasiveness, and borderline Brenner tumor is defined as "displaying epithelial proliferation beyond that seen in benign Brenner's tumor, but lacking stromal invasion." Borderline Brenner tumors are rare. Fewer than 60 cases have been reported. The more recent articles mostly focus on pathogenesis. We reviewed the literature on borderline Brenner tumor and have summarized the clinical and pathologic findings, as well as the treatment, differential diagnoses, and recent advances in histogenesis and molecular pathogenesis.
Topics: Brenner Tumor; Diagnosis, Differential; Epithelium; Female; Humans; Ovarian Neoplasms; Ovary
PubMed: 30779594
DOI: 10.5858/arpa.2018-0285-RS -
Journal of Clinical Oncology : Official... May 2015The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has...
PURPOSE
The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma.
PATIENTS AND METHODS
We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) -positive sarcoma received escalating doses (1 × 10(4)/m(2) to 1 × 10(8)/m(2)) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ζ signaling domain (HER2-CAR T cells).
RESULTS
We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 × 10(5)/m(2)) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 × 10(6)/m(2) HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months).
CONCLUSION
This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence.
Topics: Adolescent; Adult; Bone Neoplasms; Child; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Neoplasm Metastasis; Neuroectodermal Tumors; Osteosarcoma; Positron-Emission Tomography; Receptor, ErbB-2; Receptors, Antigen, T-Cell; Recurrence; Sarcoma; Sarcoma, Ewing; T-Lymphocytes; Tomography, X-Ray Computed; Treatment Outcome; Young Adult
PubMed: 25800760
DOI: 10.1200/JCO.2014.58.0225 -
Journal For Immunotherapy of Cancer Jan 2023Cell therapies for solid tumors are thwarted by the hostile tumor microenvironment (TME) and by heterogeneous expression of tumor target antigens. We address both...
BACKGROUND
Cell therapies for solid tumors are thwarted by the hostile tumor microenvironment (TME) and by heterogeneous expression of tumor target antigens. We address both limitations with a novel class of chimeric antigen receptors based on plant lectins, which recognize the aberrant sugar residues that are a 'hallmark' of both malignant and associated stromal cells. We have expressed in T cells a modified lectin from banana, H84T BanLec, attached to a chimeric antigen receptor (H84T-CAR) that recognizes high-mannose (asparagine residue with five to nine mannoses). Here, we tested the efficacy of our novel H84T CAR in models of pancreatic ductal adenocarcinoma (PDAC), intractable tumors with aberrant glycosylation and characterized by desmoplastic stroma largely contributed by pancreatic stellate cells (PSCs).
METHODS
We transduced human T cells with a second-generation retroviral construct expressing the H84T BanLec chimeric receptor, measured T-cell expansion, characterized T-cell phenotype, and tested their efficacy against PDAC tumor cells lines by flow cytometry quantification. In three-dimensional (3D) spheroid models, we measured H84T CAR T-cell disruption of PSC architecture, and T-cell infiltration by live imaging. We tested the activity of H84T CAR T cells against tumor xenografts derived from three PDAC cell lines. Antitumor activity was quantified by caliper measurement and bioluminescence signal and used anti-human vimentin to measure residual PSCs.
RESULTS
H84T BanLec CAR was successfully transduced and expressed by T cells which had robust expansion and retained central memory phenotype in both CD4 and CD8 compartments. H84T CAR T cells targeted and eliminated PDAC tumor cell lines. They also disrupted PSC architecture in 3D models in vitro and reduced total tumor and stroma cells in mixed co-cultures. H84T CAR T cells exhibited improved T-cell infiltration in multicellular spheroids and had potent antitumor effects in the xenograft models. We observed no adverse effects against normal tissues.
CONCLUSIONS
T cells expressing H84T CAR target malignant cells and their stroma in PDAC tumor models. The incorporation of glycan-targeting lectins within CARs thus extends their activity to include both malignant cells and their supporting stromal cells, disrupting the TME that otherwise diminishes the activity of cellular therapies against solid tumors.
Topics: Humans; Musa; Lectins; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; T-Lymphocytes; Receptors, Chimeric Antigen; Tumor Microenvironment
PubMed: 36653070
DOI: 10.1136/jitc-2022-005891