Metabolic reprogramming and cancer progression Faubert, Brandon; Solmonson, Ashley; DeBerardinis, Ralph J
Science (American Association for the Advancement of Science),
04/2020, Letnik:
368, Številka:
6487
Journal Article
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Metabolic reprogramming is a hallmark of malignancy. As our understanding of the complexity of tumor biology increases, so does our appreciation of the complexity of tumor metabolism. Metabolic ...heterogeneity among human tumors poses a challenge to developing therapies that exploit metabolic vulnerabilities. Recent work also demonstrates that the metabolic properties and preferences of a tumor change during cancer progression. This produces distinct sets of vulnerabilities between primary tumors and metastatic cancer, even in the same patient or experimental model. We review emerging concepts about metabolic reprogramming in cancer, with particular attention on why metabolic properties evolve during cancer progression and how this information might be used to develop better therapeutic strategies.
Somatic mutations activating telomerase reverse-trancriptase promoter were recently identified in several tumour types. Here we identify frequent similar mutations in human hepatocellular carcinomas ...(59%), cirrhotic preneoplastic macronodules (25%) and hepatocellular adenomas with malignant transformation in hepatocellular carcinomas (44%). In hepatocellular tumours, telomerase reverse-transcripase- and CTNNB1-activating mutations are significantly associated. Moreover, preliminary data suggest that telomerase reverse-trancriptase promoter mutations can increase the expression of telomerase transcript. In conclusion, telomerase reverse-trancriptase promoter mutation is the earliest recurrent genetic event identified in cirrhotic preneoplastic lesions so far and is also the most frequent genetic alteration in hepatocellular carcinomas, arising from both the cirrhotic or non-cirrhotic liver.
We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the ...translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5' untranslated regions in cancer, and expose new targets for therapeutic intervention.
Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here ...we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer.
To inform treatment decisions in women diagnosed with endometrial hyperplasia, quantification of the potential for concurrent endometrial cancer and the future risk of progression to cancer is ...required.
We identified studies up to September 2018 that reported on the prevalence of concurrent cancer (within three months of endometrial hyperplasia diagnosis), or the incidence of cancer, identified at least three months after hyperplasia diagnosis. Random-effects meta-analyses produced pooled estimates and 95% confidence intervals (CIs).
A total of 36 articles were identified; 15 investigating concurrent and 21 progression to cancer. In pooled analysis of 11 studies of atypical hyperplasia, the pooled prevalence of concurrent endometrial cancer was 32.6% (95% CI: 24.1%, 42.4%) while no studies evaluated concurrent cancer in non-atypical hyperplasia. The risk of progression to cancer was high in atypical hyperplasia (n = 5 studies, annual incidence rate = 8.2%, 95% CI 3.9%, 17.3%) and only one study reported on non-atypical hyperplasia (annual incidence rate = 2.6%, 95% CI: 0.6%, 10.6%).
Overall, a third of women with atypical hyperplasia had concurrent endometrial cancer, although the number of studies, especially population-based, is small. Progression to cancer in atypical hyperplasia was high, but few studies were identified. Population-based estimates are required, in both atypical and non-atypical hyperplasia patients to better inform treatment strategies.
Epithelial cells have an ability termed 'cell competition', which is an immune surveillance-like function that extrudes precancerous cells from the epithelial layer, leading to apoptosis and ...clearance. However, it remains unclear how epithelial cells recognize and extrude transformed cells. Here, we discovered that a PirB family protein, leukocyte immunoglobulin-like receptor B3 (LILRB3), which is expressed on non-transformed epithelial cells, recognizes major histocompatibility complex class I (MHC class I) that is highly expressed on transformed cells. MHC class I interaction with LILRB3 expressed on normal epithelial cells triggers an SHP2-ROCK2 pathway that generates a mechanical force to extrude transformed cells. Removal of transformed cells occurs independently of natural killer (NK) cell or CD8
cytotoxic T cell-mediated activity. This is a new mechanism in that the immunological ligand-receptor system generates a mechanical force in non-immune epithelial cells to extrude precancerous cells in the same epithelial layer.
The roles of intravisceral and subcutaneous fat are unknown, and the prevalence of precancerous lesions in obese patients was never evaluated. This study aims to assess the frequency and severity of ...pancreatic intraepithelial neoplasia (PanIN) and to correlate pathologic findings with metabolic abnormalities, type of fat, and fatty pancreatic infiltration.
Normal pancreatic tissue from surgical specimens was analyzed. Fatty infiltration and fibrosis in intra- and extralobular locations and PanIN lesions were assessed. General characteristics were collected: body mass index (BMI), diabetes, and tobacco intake. Liver steatosis and subcutaneous and intravisceral fat were assessed by CT scan (ImageJ software).
Of note, 110 patients were included median age, 53.8 (17-85) years. Arterial hypertension, diabetes, and tobacco intake were found in 19%, 9%, and 23%, respectively. Median BMI was 24 (16-37; BMI < 25: 45%, 25 ≤ 30: 24%, ≥30: 11%). Overall, PanIN lesions were found in 65% (type I, II, and III PanIN in 62%, 38%, and 1%, respectively). Fibrosis and fatty pancreas (intra- and extralobular locations) were found in 1% and 24% and in 30% and 51%, respectively. A correlation was observed between PanIN lesions and fatty pancreas extralobular (0.01) and intralobular (<0.0001), intralobular fibrosis (0.003), high BMI (P = 0.02), and subcutaneous (P = 0.02) and intravisceral fat (P = 0.02). The number of PanIN lesions was correlated with intravisceral fat (r = 0.22, P = 0.04), but not with subcutaneous fat (r = 0.14, P = 0.22). In multivariate analysis, PanIN lesions were associated with intralobular fibrosis OR, 5.61; 95% confidence interval (CI), 1.18-42.99 and intralobular fat (OR, 17.86; 95% CI, 4.935-88.12).
Obesity (especially android obesity) and pancreatic fatty infiltration are risk factors for pancreatic precancerous lesions.
Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide ...disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.
Despite major improvements concerning its diagnosis and treatment,pancreatic ductal adenocarcinoma(PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology,as interface ...discipline between basic and clinical medicine,has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition,by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC,a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC.This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results.Finally,recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response.The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.
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