Evolving Cancer Classification in the Era of Personalized Medicine: A Primer for Radiologists

O’Neill, Ailbhe C.; Jagannathan, Jyothi P.; Ramaiya, Nikhil H.

doi:10.3348/kjr.2017.18.1.6

Cited by 12 publications

(9 citation statements)

References 61 publications

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“…Yet, a molecular definition of AT signatures that defines metabolically-unhealthy obese sub-phenotype(s) has not been systematically attempted. In oncology, molecular typing of tumors largely relies on the identification of different tumors' genetic perturbations, increasingly used to guide patients' management [51] . Genetic polymorphisms related to obesity sub-phenotypes and/or responses to therapy are just beginning to be unraveled [52] .…”

Section: Discussionmentioning

confidence: 99%

ASK1 (MAP3K5) is transcriptionally upregulated by E2F1 in adipose tissue in obesity, molecularly defining a human dys-metabolic obese phenotype

Haim

Blüher

Konrad

et al. 2017

Molecular Metabolism

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ObjectiveObesity variably disrupts human health, but molecular-based patients' health-risk stratification is limited. Adipose tissue (AT) stresses may link obesity with metabolic dysfunction, but how they signal in humans remains poorly-characterized. We hypothesized that a transcriptional AT stress-signaling cascade involving E2F1 and ASK1 (MAP3K5) molecularly defines high-risk obese subtype.MethodsASK1 expression in human AT biopsies was determined by real-time PCR analysis, and chromatin immunoprecipitation (ChIP) adopted to AT explants was used to evaluate the binding of E2F1 to the ASK1 promoter. Dual luciferase assay was used to measure ASK1 promoter activity in HEK293 cells. Effects of E2F1 knockout/knockdown in adipocytes was assessed utilizing mouse-embryonal-fibroblasts (MEF)-derived adipocyte-like cells from WT and E2F1−/− mice and by siRNA, respectively. ASK1 depletion in adipocytes was studied in MEF-derived adipocyte-like cells from WT and adipose tissue-specific ASK1 knockout mice (ASK1-ATKO).ResultsHuman visceral-AT ASK1 mRNA (N = 436) was associated with parameters of obesity-related cardio-metabolic morbidity. Adjustment for E2F1 expression attenuated the association of ASK1 with fasting glucose, insulin resistance, circulating IL-6, and lipids (triglycerides, HDL-cholesterol), even after adjusting for BMI. Chromatin-immunoprecipitation in human-AT explants revealed BMI-associated increased occupancy of the ASK1 promoter by E2F1 (r2 = 0.847, p < 0.01). In adipocytes, siRNA-mediated E2F1-knockdown, and MEF-derived adipocytes of E2F1-knockout mice, demonstrated decreased ASK1 expression and signaling to JNK. Mutation/truncation of an E2F1 binding site in hASK1 promoter decreased E2F1-induced ASK1 promoter activity, whereas E2F1-mediated sensitization of ASK1 promoter to further activation by TNFα was inhibited by JNK-inhibitor. Finally, MEF-derived adipocytes from adipocyte-specific ASK1-knockout mice exhibited lower leptin and higher adiponectin expression and secretion, and resistance to the effects of TNFα.ConclusionsAT E2F1 –ASK1 molecularly defines a metabolically-detrimental obese sub-phenotype. Functionally, it may negatively affect AT endocrine function, linking AT stress to whole-body metabolic dysfunction.

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Section: Discussionmentioning

confidence: 99%

ASK1 (MAP3K5) is transcriptionally upregulated by E2F1 in adipose tissue in obesity, molecularly defining a human dys-metabolic obese phenotype

Haim

Blüher

Konrad

et al. 2017

Molecular Metabolism

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“…Solid tumors are classified according to the type of cells forming the tumor, where localized solid tumors are either sarcoma, carcinoma, or lymphoma (1). Solid tumor cancers directly affect patient survival, particularly when tumors are malignant (2).…”

Section: Introductionmentioning

confidence: 99%

Baicalein inhibits tumor progression by inhibiting tumor cell growth and tumor angiogenesis

et al. 2017

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Abstract. Baicalein, a herbal medicine, is a natural flavonoid isolated from the roots of Scutellaria baicalensis Georgi. It is known for its anticancer, anti-inflammatory and neuroprotective properties. Despite these well-known properties, it is not yet clear what effect baicalein has on tumor progression. Therefore, in the present study, we used B16F10 cells, Lewis lung carcinoma (LLC) cells, and human umbilical vein endothelial cells (HUVECs) to investigate the effect of baicalein on cell proliferation and viability, migration and tube formation in vitro. In addition, an experimental animal model was used to observe the growth rate and metastasis of tumors and tumor vessel formation in vivo. Our results showed that baicalein decreased the proliferation and migration and induced tumor cell death via caspase-3 activation in the B16F10 and LLC cells, and strongly inhibited tube formation and cell migration in HUVECs. Furthermore, mouse models showed that baicalein reduced the tumor volume and greatly reduced the tumor growth rate in the early stages of tumor progression, and the baicalein-treated groups had significantly reduced expression of CD31 (endothelial cell marker) and α-SMA (mural cell marker) in the tumors, indicating that baicalein inhibits tumor angiogenesis by disrupting tumor vasculature development. Comparison of the lymph node and lung samples collected from the baicalein-treated group, and the untreated group showed that baicalein reduced metastasis of the tumor to these tissues. In summary, baicalein reduced tumor progression and metastasis, directly induced tumor cell death, and inhibited tumor angiogenesis. Our results strongly demonstrate that baicalein is a potential chemotherapeutic agent.

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“…Many studies have addressed the clinico-pathologic characteristics of IMAs as an evolving disease entity. Particularly, in terms of genetic profile, IMA is correlated with the absence of epidermal growth factor receptor (EGFR) mutations and the presence of KRAS mutations, which indicates that these tumors are unlikely to respond to EGFR-tyrosine kinase inhibitors such as gefitinib and erlotinib (4512212223). Many reports have also shown that IMA is associated with lower rates of pleural involvement, lymphatic permeation, and vascular invasion, in contrast to frequent aerogenous spread (6781124).…”

Section: Discussionmentioning

confidence: 99%

Solitary Nodular Invasive Mucinous Adenocarcinoma of the Lung: Imaging Diagnosis Using the Morphologic-Metabolic Dissociation Sign

et al. 2019

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Objective To evaluate the efficacy of the morphologic-metabolic (M-M) dissociation sign based on computed tomography (CT) and fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/CT in discriminating invasive mucinous adenocarcinoma (IMA) from invasive non-mucinous adenocarcinomas (ADCs) of the lung. Materials and Methods The Institutional Review Board approved this retrospective study. Among surgically resected solitary pulmonary nodule (SPN)-type ADCs (< 3 cm in diameter), 35 patients with IMAs and 329 with invasive non-mucinous ADCs were included. Morphologic malignancy was established if the tumor with lobulated or spiculated margin on CT presented a tumor shadow disappearance rate of < 0.5. The M-M dissociation sign was determined when a malignant-morphologic nodule on CT showed maximum standardized uptake value (SUVmax) < 3.5 on PET/CT. Results Among 35 IMAs (size: 21 ± 7 mm, SUVmax: 1.8 ± 2.0) and 329 invasive non-mucinous ADCs (size: 21 ± 6 mm, SUVmax: 4.6 ± 4.2), the M-M dissociation sign was observed in 54% of IMAs (19/35) and 10% of invasive non-mucinous ADCs (34/329) ( p < 0.001). The diagnostic performance of the sign in discriminating IMA from invasive non-mucinous ADCs showed a sensitivity of 54.3% (95% confidence interval [CI], 36.7–71.2), specificity 89.7% (95% CI, 85.9–92.7), positive predictive value 35.8% (95% CI, 26.5–46.5), and negative predictive value 94.9% (95% CI, 92.8–96.4). Multivariate analyses revealed metabolic benignity (odds ratio [OR] 2.99; 95% CI, 1.01–8.93; p = 0.047) and M-M dissociation sign (OR 6.35; 95% CI, 2.76–14.62; p < 0.001) to be significant predictors of SPN-type IMAs. Conclusion Identification of the absence of M-M dissociation sign is an accurate indicator for excluding IMA from SPN-type lung ADCs.

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Evolving Cancer Classification in the Era of Personalized Medicine: A Primer for Radiologists

Cited by 12 publications

References 61 publications

ASK1 (MAP3K5) is transcriptionally upregulated by E2F1 in adipose tissue in obesity, molecularly defining a human dys-metabolic obese phenotype

ASK1 (MAP3K5) is transcriptionally upregulated by E2F1 in adipose tissue in obesity, molecularly defining a human dys-metabolic obese phenotype

Baicalein inhibits tumor progression by inhibiting tumor cell growth and tumor angiogenesis

Solitary Nodular Invasive Mucinous Adenocarcinoma of the Lung: Imaging Diagnosis Using the Morphologic-Metabolic Dissociation Sign

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