-
Human Pathology Feb 2023Low-grade appendiceal mucinous neoplasms are unique tumors of the appendix, characterized by low-grade mucinous epithelium with villiform, undulating, or flat... (Review)
Review
Low-grade appendiceal mucinous neoplasms are unique tumors of the appendix, characterized by low-grade mucinous epithelium with villiform, undulating, or flat architecture. These tumors lack infiltrative growth or destructive invasion, but can extend into the appendiceal wall by a "pushing" pattern of invasion, with a broad front that can mimic a diverticulum. These neoplasms have a propensity for peritoneal dissemination, resulting in the clinical presentation of pseudomyxoma peritonei. The pathologic staging of these neoplasms is challenging and fraught with confusing terminology and numerous classification systems. This review focuses on the AJCC pathologic staging of these tumors with a focus on challenging situations.
Topics: Humans; Peritoneal Neoplasms; Pseudomyxoma Peritonei; Appendiceal Neoplasms; Appendix; Neoplasms, Glandular and Epithelial
PubMed: 35843338
DOI: 10.1016/j.humpath.2022.07.004 -
Clinical and Translational Medicine Jun 2021Gallbladder cancer (GC) is a malignant disease characterized with highly cellular heterogeneity and poor prognosis. Determining the intratumoral heterogeneity and...
BACKGROUND
Gallbladder cancer (GC) is a malignant disease characterized with highly cellular heterogeneity and poor prognosis. Determining the intratumoral heterogeneity and microenvironment (TME) can provide novel therapeutic strategies for GC.
METHODS
We performed the single-cell RNA sequencing on the primary and lymph node metastatic gallbladder tumors and the adjacent normal tissues of five patients. The transcriptomic atlas and ligand-receptor-based intercellular communication networks of the single cells were characterized.
RESULTS
The transcriptomic landscape of 24,887 single cells was obtained and characterized as 10 cellular clusters, including epithelial, neuroendocrine tumor cells, T&NK cells, B cells, RGS5+ fibroblasts, POSTN+ fibroblasts, PDGFRA+ fibroblasts, endothelial, myeloid cells, and mast cells. Different types of GC harbored distinct epithelial tumor subpopulations, and squamous cell carcinoma could be differentiated from adenocarcinoma cells. Abundant immune cells infiltrated into adenocarcinoma and squamous cell carcinoma, rather than neuroendocrine neoplasms, which showed significant enrichment of stromal cells. CD4+/FOXP3+ T-reg and CD4+/CXCL13+ T helper cells with higher exhausting biomarkers, as well as a dynamic lineage transition of tumor-associated macrophages from CCL20 /CD163 , CCL20 /CD163 to APOE+, were identified in GC tissues, suggesting the immunosuppressive and tumor-promoting status of immune cells in TME. Two distinct endothelial cells (KDR+ and ACKR1+), which were involved in angiogenesis and lymphangiogenesis, showed remarkable ligand-receptor interactions with primary GC cells and macrophages in gallbladder tumors.
CONCLUSIONS
This study reveals a widespread reprogramming across multiple cell populations in GC progression, dissects the cellular heterogeneity and interactions in gallbladder TME, and provides potential therapeutic targets for GC.
Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Squamous Cell; Disease Progression; Female; Follow-Up Studies; Gallbladder Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Myeloid Cells; Neoplasms, Glandular and Epithelial; Neuroendocrine Tumors; Prognosis; Single-Cell Analysis; Stromal Cells; Survival Rate; Transcriptome; Tumor Cells, Cultured; Tumor Microenvironment
PubMed: 34185421
DOI: 10.1002/ctm2.462 -
American Society of Clinical Oncology... 2017Our understanding of epithelial ovarian cancer has blossomed, and we now recognize that it is a collection of varied histologic and molecularly different malignancies,... (Review)
Review
Our understanding of epithelial ovarian cancer has blossomed, and we now recognize that it is a collection of varied histologic and molecularly different malignancies, many of which may not derive from a true ovarian anatomic precursor. High-grade serous ovarian cancer (HGSOC) is a unique type of epithelial cancer. It is characterized by nearly universal mutation in and dysfunction of p53, genomic instability rather than driver mutations, advanced stage at onset, and probable fallopian tube epithelium origin, with a serous tubal in situ carcinoma precursor. Germline deleterious mutations in BRCA1 and BRCA2, as well as other less prevalent genes involved in DNA repair, such as PALB2 and RAD51c, are associated with its carcinogenesis and may predict susceptibility to classes of treatment agents, including DNA-damaging agents and DNA repair inhibitors. Loss of function of these genes is associated with homologous recombination dysfunction (HRD). It is now recognized that there may be HGSOC with wild-type BRCA1 and BRCA2 with an identifiable HRD phenotype. Such HRD tumors also may be more susceptible to certain classes of treatments and may be phenotypically detectable with a composite molecular biomarker that has been shown to be predictive for response to PARP inhibitors. Use of this new knowledge of the anatomic and molecular background of HGSOC has led to the rational design of novel combinations of treatment classes to create an HRD-like cellular environment and thus drive treatment benefits.
Topics: BRCA1 Protein; BRCA2 Protein; Carcinoma, Ovarian Epithelial; Cystadenocarcinoma, Serous; DNA Repair; DNA-Binding Proteins; Fallopian Tubes; Fanconi Anemia Complementation Group N Protein; Female; Germ-Line Mutation; Humans; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Tumor Suppressor Protein p53
PubMed: 28561656
DOI: 10.1200/EDBK_174718 -
Expert Opinion on Biological Therapy Nov 2022High-grade serous ovarian carcinoma (HGSC) is an aggressive subtype of epithelial ovarian carcinoma (EOC) and remains the most lethal gynecologic cancer. A lack of...
INTRODUCTION
High-grade serous ovarian carcinoma (HGSC) is an aggressive subtype of epithelial ovarian carcinoma (EOC) and remains the most lethal gynecologic cancer. A lack of effective and tolerable therapeutic options and nonspecific symptoms at presentation with advanced stage of disease are among the challenges in the management of the disease.
AREAS COVERED
An overview of ovarian cancer, followed by a discussion of the current therapeutic regimes and challenges that arise during and after the treatment of EOC. We discuss different formats of antibody therapeutics and their usage in targeting validated targets implicated in ovarian cancer, as well as three emerging novel proteins as examples recently implicated in their contribution to adaptive resistance in ovarian cancer.
EXPERT OPINION
Antibody therapeutics allow for a unique and effective way to target proteins implicated in cancer and other diseases, and have the potential to radically change the outcomes of patients suffering from ovarian cancer. The vast array of targets that have been implicated in ovarian cancer and yet the lack of effective therapeutic options for patients further stresses the importance of discovering novel proteins that can be targeted, as well as predictive biomarkers that can inform the stratification of patients into treatment-specific populations.
Topics: Humans; Female; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Neoplasms, Glandular and Epithelial
PubMed: 36302510
DOI: 10.1080/14712598.2022.2141565 -
Chinese Journal of Cancer Jan 2015In this issue of the Chinese Journal of Cancer, European, American, and Chinese experts review the current management and future perspectives of epithelial ovarian...
In this issue of the Chinese Journal of Cancer, European, American, and Chinese experts review the current management and future perspectives of epithelial ovarian cancer (EOC), the leading cause of gynecological cancer deaths. Although major advances have been made in understanding the cellular and molecular biology of this highly heterogeneous malignancy, the survival rate of women with EOC has changed little since the introduction of platinum-based treatment as a front-line therapy. The papers describe the progress in deciphering the molecular complexity of this disease and the newly available molecular-driven therapies, which have been applied by shifting trial designs toward restricting eligibility to specific subgroups of patients rather than testing agents in unselected populations. These new trial designs provide potential opportunities for improved efficacy in targeted populations. Given the molecular complexity of this disease, patient survival may be increased by searching for new molecular prognostic/predictive signatures as well as by translating the recent insight of microRNA involvement in EOC progression into new, targeted therapies. Particular attention has been given to the issue of fertility sparing for women affected by curable diseases.
Topics: Carcinoma, Ovarian Epithelial; Female; Humans; MicroRNAs; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms
PubMed: 25556613
DOI: 10.5732/cjc.014.10301 -
Oncotarget Feb 2017The cell surface membrane-bound mucin protein MUC4 promotes tumorigenicity, aggressive behavior, and poor outcomes in various types of epithelial carcinomas, including... (Review)
Review
The cell surface membrane-bound mucin protein MUC4 promotes tumorigenicity, aggressive behavior, and poor outcomes in various types of epithelial carcinomas, including pancreatic, breast, colon, ovarian, and prostate cancer. This review summarizes the theories and findings regarding MUC4 function, and its role in epithelial carcinogenesis. Based on these insights, we developed an outline of the processes and mechanisms by which MUC4 critically supports the propagation and survival of cancer cells in various epithelial organs. MUC4 may therefore be a useful prognostic and diagnostic tool that improves our ability to eradicate various forms of cancer.
Topics: Animals; Carcinoma; Cell Membrane; Cell Transformation, Neoplastic; Humans; Mucin-4; Neoplasms, Glandular and Epithelial
PubMed: 27829225
DOI: 10.18632/oncotarget.13122 -
Nature Reviews. Clinical Oncology Apr 2013The natural history of ovarian cancer continues to be characterized by late-stage presentation, metastatic bulky disease burden and stagnant mortality statistics,... (Review)
Review
The natural history of ovarian cancer continues to be characterized by late-stage presentation, metastatic bulky disease burden and stagnant mortality statistics, despite prolific drug development. Robust clinical investigation, particularly with modifications to primary treatment surgical goals and adjuvant therapy are increasing median progression-free survival and overall survival, although the cure rates have been affected only modestly. Maintenance therapy holds promise, but studies have yet to identify an agent and/or strategy that can affect survival. Recurrent disease is largely an incurable state; however, current intervention with selected surgery, combination and targeted therapy and investigational protocols are impacting progression-free survival. Ovarian cancer is a diverse and genomically complex disease, which commands global attention. Rational investigation must balance the high rate of discovery with lagging clinical investigation and limited patient resources. Nevertheless, growth in our armamentarium offers unprecedented opportunities for patients suffering with this disease. This Review presents and reviews the contemporary management of the disease spectrum termed epithelial 'ovarian' cancer and describes the direction and early results of clinical investigation.
Topics: Biomedical Research; Carcinoma, Ovarian Epithelial; Combined Modality Therapy; Female; Humans; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms
PubMed: 23381004
DOI: 10.1038/nrclinonc.2013.5 -
Cancer Control : Journal of the Moffitt... Jan 2011Angiogenesis is a critical component of tumor development and proliferation, and increased angiogenesis has been associated with a worse clinical outcome in a number of... (Review)
Review
BACKGROUND
Angiogenesis is a critical component of tumor development and proliferation, and increased angiogenesis has been associated with a worse clinical outcome in a number of solid tumors, including ovarian cancer. Therefore, agents that target the angiogenic process are of considerable interest in the treatment of ovarian cancer.
METHODS
Studies evaluating the efficacy of antiangiogenic agents in ovarian cancer are reported. Antiangiogenic agents examined include vascular endothelial growth factor (VEGF) pathway inhibitors, including monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and a soluble receptor decoy, as well as inhibitors of other angiogenic factors and vascular disrupting agents.
RESULTS
The VEGF inhibitor bevacizumab has been shown to have efficacy in ovarian cancer in phase II trials and a progression-free survival advantage in one phase III trial. TKIs block the VEGF receptors and secondary angiogenic pathways and have shown activity in phase I and II trials. Alternative angiogenesis inhibitors include EphA2 inhibitors and a selective angiopoietin 1/2-neutralizing peptibody. Another strategy is to destroy the existing tumor vasculature, and a number of vascular disrupting agents are being studied in preclinical and phase I trials. Antiangiogenic agents have a unique side effect profile, likely due to inhibition of normal physiologic angiogenesis.
CONCLUSIONS
Phase II and early phase III trials have demonstrated that antiangiogenic therapies have significant activity in ovarian cancer. The results of phase III trials in the front-line and recurrent settings will determine the extent of clinical benefit of antiangiogenic therapies in combination with chemotherapy. Antiangiogenic agents have a distinct side effect profile, and further studies are necessary to evaluate how to minimize the incidence of these events and to identify women most likely to benefit from these therapies.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Female; Humans; Neoplasms, Glandular and Epithelial; Neovascularization, Pathologic; Ovarian Neoplasms
PubMed: 21273978
DOI: 10.1177/107327481101800105 -
Gynecologic Oncology Nov 2018Ovarian clear cell carcinoma (OCCC) is distinctive from other histological types of epithelial ovarian cancer, with genetic/epigenetic alterations, a specific... (Review)
Review
Ovarian clear cell carcinoma (OCCC) is distinctive from other histological types of epithelial ovarian cancer, with genetic/epigenetic alterations, a specific immune-related molecular profile, and epidemiologic associations with ethnicity and endometriosis. These findings allow for the exploration of unique and specific treatments for OCCC. Two major mutated genes in OCCC are PIK3CA and ARID1A, which are frequently coexistent with each other. Other genes' alterations also contribute to activation of the PI3K (e.g. PIK3R1 and PTEN) and dysregulation of the chromatin remodeling complex (e.g. ARID1B, and SMARKA4). Although the number of focal copy number variations is small in OCCC, amplification is recurrently detected at chromosome 20q13.2 (including ZNF217), 8q, and 17q. Both expression and methylation profiling highlight the significance of adjustments to oxidative stress and inflammation. In particular, up-regulation of HNF-1β resulting from hypomethylation contributes to the switch from anaerobic to aerobic glucose metabolism. Additionally, up-regulation of HNF-1β activates STAT3 and NF-κB signaling, and leads to immune suppression via production of IL-6 and IL-8. Immune suppression may also be induced by the increased expression of PD-1, Tim-3 and LAG3. Mismatch repair deficient (microsatellite instable) tumors as found in Lynch syndrome also induce immune suppression in some OCCC. In a recent phase II clinical trial in heavily-treated platinum-resistant ovarian cancer, two out of twenty cases with a complete response to the anti-PD-1 antibody, nivolumab, were OCCC subtypes. Thus, the immune-suppressive state resulting from both genetic alterations and the unique tumor microenvironment may be associated with sensitivity to immune checkpoint inhibitors in OCCC. In this review, we highlight recent update and progress in OCCC from both the genomic and immunologic points of view, addressing the future candidate therapeutic options.
Topics: Adenocarcinoma, Clear Cell; Carcinoma, Ovarian Epithelial; Female; Genomics; Humans; Immunotherapy; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms
PubMed: 30217369
DOI: 10.1016/j.ygyno.2018.09.001 -
International Journal of Molecular... Jul 2018Metabolism is deeply involved in cell behavior and homeostasis maintenance, with metabolites acting as molecular intermediates to modulate cellular functions. In... (Review)
Review
Metabolism is deeply involved in cell behavior and homeostasis maintenance, with metabolites acting as molecular intermediates to modulate cellular functions. In particular, one-carbon metabolism is a key biochemical pathway necessary to provide carbon units required for critical processes, including nucleotide biosynthesis, epigenetic methylation, and cell redox-status regulation. It is, therefore, not surprising that alterations in this pathway may acquire fundamental importance in cancer onset and progression. Two of the major actors in one-carbon metabolism, folate and choline, play a key role in the pathobiology of epithelial ovarian cancer (EOC), the deadliest gynecological malignancy. EOC is characterized by a cholinic phenotype sustained via increased activity of choline kinase alpha, and via membrane overexpression of the alpha isoform of the folate receptor (FRα), both of which are known to contribute to generating regulatory signals that support EOC cell aggressiveness and proliferation. Here, we describe in detail the main biological processes associated with one-carbon metabolism, and the current knowledge about its role in EOC. Moreover, since the cholinic phenotype and FRα overexpression are unique properties of tumor cells, but not of normal cells, they can be considered attractive targets for the development of therapeutic approaches.
Topics: Carbon; Carcinoma, Ovarian Epithelial; Choline; Female; Folic Acid; Humans; Models, Biological; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms
PubMed: 30029471
DOI: 10.3390/ijms19072092