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Journal of Hepatology Aug 2023Hepatocellular carcinoma (HCC), a leading cause of cancer-related death, is associated with viral hepatitis, non-alcoholic steatohepatitis (NASH), and alcohol-related...
BACKGROUND & AIMS
Hepatocellular carcinoma (HCC), a leading cause of cancer-related death, is associated with viral hepatitis, non-alcoholic steatohepatitis (NASH), and alcohol-related steatohepatitis, all of which trigger endoplasmic reticulum (ER) stress, hepatocyte death, inflammation, and compensatory proliferation. Using ER stress-prone MUP-uPA mice, we established that ER stress and hypernutrition cooperate to cause NASH and HCC, but the contribution of individual stress effectors, such as activating transcription factor 4 (ATF4), to HCC and their underlying mechanisms of action remained unknown.
METHODS
Hepatocyte-specific ATF4-deficient MUP-uPA mice (MUP-uPA/Atf4) and control MUP-uPA/Atf4 mice were fed a high-fat diet to induce NASH-related HCC, and Atf4 and Atf4 mice were injected with diethylnitrosamine to model carcinogen-induced HCC. Histological, biochemical, and RNA-sequencing analyses were performed to identify and define the role of ATF4-induced solute carrier family 7a member 11 (SLC7A11) expression in hepatocarcinogenesis. Reconstitution of SLC7A11 in ATF4-deficient primary hepatocytes and mouse livers was used to study its effects on ferroptosis and HCC development.
RESULTS
Hepatocyte ATF4 ablation inhibited hepatic steatosis, but increased susceptibility to ferroptosis, resulting in accelerated HCC development. Although ATF4 activates numerous genes, ferroptosis susceptibility and hepatocarcinogenesis were reversed by ectopic expression of a single ATF4 target, Slc7a11, coding for a subunit of the cystine/glutamate antiporter xCT, which is needed for glutathione synthesis. A ferroptosis inhibitor also reduced liver damage and inflammation. ATF4 and SLC7A11 amounts were positively correlated in human HCC and livers of patients with NASH.
CONCLUSIONS
Despite ATF4 being upregulated in established HCC, it serves an important protective function in normal hepatocytes. By maintaining glutathione production, ATF4 inhibits ferroptosis-dependent inflammatory cell death, which is known to promote compensatory proliferation and hepatocarcinogenesis. Ferroptosis inhibitors or ATF4 activators may also blunt HCC onset.
IMPACT AND IMPLICATIONS
Liver cancer or hepatocellular carcinoma (HCC) is associated with multiple aetiologies. Most HCC aetiologies cause hepatocyte stress and death, as well as subsequent inflammation, and compensatory proliferation, thereby accelerating HCCdevelopment. The contribution of individual stress effectors to HCC and their underlying mechanisms of action were heretofore unknown. This study shows that the stress-responsive transcription factor ATF4 blunts liver damage and cancer development by suppressing iron-dependent cell death (ferroptosis). Although ATF4 ablation prevents hepatic steatosis, it also increases susceptibility to ferroptosis, due to decreased expression of the cystine/glutamate antiporter SLC7A11, whose expression in human HCC and NASH correlates with ATF4. These findings reinforce the notion that benign steatosis may be protective and does not increase cancer risk unless accompanied by stress-induced liver damage. These results have important implications for prevention of liver damage and cancer.
Topics: Humans; Mice; Animals; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Liver Neoplasms; Ferroptosis; Activating Transcription Factor 4; Cystine; Inflammation; Carcinogenesis; Glutamates; Amino Acid Transport System y+
PubMed: 36996941
DOI: 10.1016/j.jhep.2023.03.016 -
Archives of Pathology & Laboratory... Dec 2023Salivary gland neoplasms are rare lesions in the head and neck (H&N) pathology realm. There are more than 20 malignant and 15 benign salivary gland neoplasms in the 5th... (Review)
Review
CONTEXT.—
Salivary gland neoplasms are rare lesions in the head and neck (H&N) pathology realm. There are more than 20 malignant and 15 benign salivary gland neoplasms in the 5th edition of the World Health Organization classification of H&N tumors. These neoplasms consist of heterogeneous groups of uncommon diseases that make diagnosis and treatment challenging for the clinical team. Using an algorithmic immunohistochemical approach-defined tumor origin and type has proven to be effective and advantageous. Immunohistochemistry may be used as sort of a "diagnostic looking glass," not as a positive or negative type tool, but as an indispensable complement to a hematoxylin-eosin morphologic pattern-based approach. Furthermore, the understanding of the novel discoveries of the salivary gland gene fusions and the molecular aspects of these tumors makes the process easier and improve the diagnosis as well as treatment aspects. This review reflects our experience with more recent diagnostic antibodies, which include MYB RNA, Pan-TRK, PLAG1, LEF1, and NR4A3. Each of these is linked with a specific type of neoplasm; for example, gene fusions involving the PLAG1 and HMGA2 oncogenes are specific for benign pleomorphic adenomas, and MYB is associated with adenoid cystic carcinoma.
OBJECTIVE.—
To review these more recent antibodies, which highly enhance salivary gland neoplasm diagnosis.
DATA SOURCES.—
The study sources involved literature PubMed searches, including multiple review articles, case reports, selected book chapters, and Geisinger Medical Center cases.
CONCLUSIONS.—
Salivary gland tumors are a rare, varied group of lesions in H&N pathology. We need to have continuous readings and revisions of the molecular consequences of these fusion oncoproteins and their subsequent targets, which will eventually lead to the identification of novel driver genes in salivary gland neoplasms.
Topics: Humans; Immunohistochemistry; Salivary Gland Neoplasms; Adenoma, Pleomorphic; Salivary Glands; Carcinoma, Adenoid Cystic; Transcription Factors; Biomarkers, Tumor
PubMed: 37074867
DOI: 10.5858/arpa.2022-0461-RA -
Virchows Archiv : An International... Jul 2023The heterogeneous group of B3 lesions in the breast harbors lesions with different malignant potential and progression risk. As several studies about B3 lesions have... (Review)
Review
The heterogeneous group of B3 lesions in the breast harbors lesions with different malignant potential and progression risk. As several studies about B3 lesions have been published since the last Consensus in 2018, the 3rd International Consensus Conference discussed the six most relevant B3 lesions (atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), classical lobular neoplasia (LN), radial scar (RS), papillary lesions (PL) without atypia, and phyllodes tumors (PT)) and made recommendations for diagnostic and therapeutic approaches. Following a presentation of current data of each B3 lesion, the international and interdisciplinary panel of 33 specialists and key opinion leaders voted on the recommendations for further management after core-needle biopsy (CNB) and vacuum-assisted biopsy (VAB). In case of B3 lesion diagnosis on CNB, OE was recommended in ADH and PT, whereas in the other B3 lesions, vacuum-assisted excision was considered an equivalent alternative to OE. In ADH, most panelists (76%) recommended an open excision (OE) after diagnosis on VAB, whereas observation after a complete VAB-removal on imaging was accepted by 34%. In LN, the majority of the panel (90%) preferred observation following complete VAB-removal. Results were similar in RS (82%), PL (100%), and FEA (100%). In benign PT, a slim majority (55%) also recommended an observation after a complete VAB-removal. VAB with subsequent active surveillance can replace an open surgical intervention for most B3 lesions (RS, FEA, PL, PT, and LN). Compared to previous recommendations, there is an increasing trend to a de-escalating strategy in classical LN. Due to the higher risk of upgrade into malignancy, OE remains the preferred approach after the diagnosis of ADH.
Topics: Humans; Female; Breast; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Mammography; Biopsy, Large-Core Needle; Precancerous Conditions; Phyllodes Tumor; Retrospective Studies
PubMed: 37330436
DOI: 10.1007/s00428-023-03566-x -
Endocrine Jun 2023The 5 edition of the World Health Organization (WHO) classification of endocrine tumors was released in 2022. Several novelties have been introduced concerning the... (Review)
Review
The 5 edition of the World Health Organization (WHO) classification of endocrine tumors was released in 2022. Several novelties have been introduced concerning the nomenclature and histopathological diagnosis of follicular-derived thyroid neoplasms. Tumor types have been sharply classified according to prognostic risk categories into benign tumors, low-risk neoplasms and malignant neoplasms. A grading system for differentiated thyroid carcinomas has been implemented with the aim of improving the stratification of tumors. Particular attention has been paid to the molecular profile of well-differentiated histotypes. In this review, the main changes introduced by the latest edition of the WHO system are presented. The practical effects on the diagnostic pathology of thyroid tumors, along with the clinical implications expected with the new classification scheme, are critically discussed.
Topics: Humans; Adenocarcinoma, Follicular; Thyroid Neoplasms; Endocrine Glands; Prognosis; World Health Organization
PubMed: 36964880
DOI: 10.1007/s12020-023-03336-4 -
Pituitary Jun 2023The majority of corticotroph adenomas are benign but some are locally invasive, demonstrate high rates of recurrence, and exhibit a relatively poor response to often... (Review)
Review
The majority of corticotroph adenomas are benign but some are locally invasive, demonstrate high rates of recurrence, and exhibit a relatively poor response to often repeated surgical, medical, and radiation treatment. Herein, we summarize the currently known somatic and genetic mutations and other molecular factors that influence the pathogenesis of these tumors and discuss currently available therapies. Although recent molecular studies have advanced our understanding of the pathogenesis and behavior of these refractory corticotroph adenomas, these insights do not reliably guide treatment choices at present. Development of additional diagnostic tools and novel tumor-directed therapies that offer efficacious treatment choices for patients with refractory corticotroph adenomas are needed.
Topics: Humans; ACTH-Secreting Pituitary Adenoma; Adenoma; Pituitary Neoplasms
PubMed: 36917358
DOI: 10.1007/s11102-023-01308-5 -
Acta Gastro-enterologica Belgica 2023Biliary papillomatosis (BP) is a rare disorder of the biliary tract characterized by the presence of multiple papillary adenomas spread along the biliary tree. Although...
Biliary papillomatosis (BP) is a rare disorder of the biliary tract characterized by the presence of multiple papillary adenomas spread along the biliary tree. Although benign, it carries a significant risk of malignant transformation. Due to low sensitivity and specificity of conventional radiologic modalities, the diagnosis as well as estimation of disease extent is difficult. Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreaticography (ERCP) are superior although direct peroral cholangioscopy (POC) is currently the most accurate diagnostic method. Mainly because it provides more detailed information and makes targeted histological diagnosis possible. The treatment of biliary papillomatosis consists of surgical resection, liver transplantation (LT) or a combination of both. Unfortunately, the recurrence rate after radical surgery without LT remains high due to the diffuse distribution of the disease.
Topics: Humans; Cholangiopancreatography, Endoscopic Retrograde; Bile Duct Neoplasms; Sensitivity and Specificity; Adenoma; Papilloma
PubMed: 37814564
DOI: 10.51821/86.3.11733