scholarly journals BRCA1/Trp53 heterozygosity and replication stress drive esophageal cancer development in a mouse model

2021 ◽  
Vol 118 (41) ◽  
pp. e2108421118
Author(s):  
Ye He ◽  
Joshua Rivera ◽  
Miklos Diossy ◽  
Haohui Duan ◽  
Christian Bowman-Colin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Squamous Cell ◽  
Tumor Model ◽  
Replication Stress ◽  
Squamous Cell Carcinomas ◽  
Mutation Rates ◽  
Wild Type ◽  
Breast And Ovarian Cancer ◽  
Esophageal Tissue ◽  
Increased Risk

BRCA1 germline mutations are associated with an increased risk of breast and ovarian cancer. Recent findings of others suggest that BRCA1 mutation carriers also bear an increased risk of esophageal and gastric cancer. Here, we employ a Brca1/Trp53 mouse model to show that unresolved replication stress (RS) in BRCA1 heterozygous cells drives esophageal tumorigenesis in a model of the human equivalent. This model employs 4-nitroquinoline-1-oxide (4NQO) as an RS-inducing agent. Upon drinking 4NQO-containing water, Brca1 heterozygous mice formed squamous cell carcinomas of the distal esophagus and forestomach at a much higher frequency and speed (∼90 to 120 d) than did wild-type (WT) mice, which remained largely tumor free. Their esophageal tissue, but not that of WT control mice, revealed evidence of overt RS as reflected by intracellular CHK1 phosphorylation and 53BP1 staining. These Brca1 mutant tumors also revealed higher genome mutation rates than those of control animals; the mutational signature SBS4, which is associated with tobacco-induced tumorigenesis; and a loss of Brca1 heterozygosity (LOH). This uniquely accelerated Brca1 tumor model is also relevant to human esophageal squamous cell carcinoma, an often lethal tumor.

Age and clear eyes are associated with an increased risk of cutaneous squamous cell carcinomas in vemurafenib-treated melanoma patients

2016 ◽  
Vol 26 (5) ◽  
pp. 487-491 ◽  
Author(s):  
Florian Herms ◽  
Nora Kramkimel ◽  
Elodie Regnier-Rosencher ◽  
Agnès Carlotti ◽  
Johan Chanal ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Squamous Cell Carcinomas ◽  
Increased Risk ◽  
Melanoma Patients

scholarly journals Dihydroisotanshinone I as a Treatment Option for Head and Neck Squamous Cell Carcinomas

2021 ◽  
Vol 22 (16) ◽  
pp. 8881
Author(s):  
Cheng-Ming Hsu ◽  
Ming-Yu Yang ◽  
Ming-Shao Tsai ◽  
Geng-He Chang ◽  
Yao-Hsu Yang ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Mouse Model ◽  
Head And Neck ◽  
Squamous Cell ◽  
Salvia Miltiorrhiza ◽  
Chinese Herb ◽  
Squamous Cell Carcinomas ◽  
Xenograft Mouse Model ◽  
Chemotherapy Drugs

Head and neck squamous cell carcinomas (HNSCCs) are the most common cancers of the head and neck, and their prevalence is rapidly increasing. HNSCCs present a clinical challenge because of their high recurrence rate, therapeutic resistance to radiation and chemotherapy drugs, and adverse effects. Hence, traditional Chinese herbal treatment may be advantageous to therapeutic strategies for HNSCCs. Danshen (Salvia miltiorrhiza), a well-known Chinese herb, has been extensively applied in treatments for various diseases, including cancer, because of its high degree of safety and low rate of adverse effects despite its unclear mechanism. Thus, we aimed to explore the possible anticancer effects and mechanisms of dihydroisotanshinone I (DT), a compound in danshen (extract from danshen), on HNSCCs. Three HNSCCs cell lines were used for in vitro studies, and a Detroit 562 xenograft mouse model was chosen for in vivo studies. Our in vitro results showed that DT could initiate apoptosis, resulting in cell death, and the p38 signaling partially regulated DT-initiated cell apoptosis in the Detroit 562 model. In the xenograft mouse model, DT reduced tumor size with no obvious adverse effect of hepatotoxicity. The present study suggests that DT is a promising novel candidate for anti-HNSCCs therapy.

scholarly journals Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 655-665 ◽  
Author(s):  
Joseph Christopher ◽  
Ann-Sofie Thorsen ◽  
Sam Abujudeh ◽  
Filipe C. Lourenço ◽  
Richard Kemp ◽  
...  
Keyword(s):  
Stem Cell ◽  
Fold Increase ◽  
Mutation Rates ◽  
Wild Type ◽  
Cell Dynamics ◽  
Tissue Samples ◽  
Age Related ◽  
Increased Risk ◽  
Microsatellite Mutation ◽  
Risk Of Cancer

Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus, and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (∼50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2-deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 × 10−2) compared to wild-type epithelium (6.2 × 10−5).

HIF-1α is a Prognostic Marker in Oral Squamous Cell Carcinomas

2010 ◽  
Vol 25 (2) ◽  
pp. 87-92 ◽  
Author(s):  
Alexander W. Eckert ◽  
Andreas Schütze ◽  
Matthias H.W. Lautner ◽  
Helge Taubert ◽  
Johannes Schubert ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Squamous Cell ◽  
Squamous Cell Carcinomas ◽  
Immunoperoxidase Technique ◽  
Prognostic Impact ◽  
Disease Specific Survival ◽  
Cox Regression Analysis ◽  
Oral Squamous Cell Carcinomas ◽  
Increased Risk ◽  
Disease Specific

The critical molecular regulator of hypoxia is the hypoxia-inducible factor 1 alpha (HIF-1α). The prognostic impact of this regulator protein in oral squamous cell carcinomas (OSCC) has not been comprehensively investigated. The aim of this study was to analyze the expression of HIF-1α in 82 patients with OSCC and to correlate it with their disease-specific survival. Immunohistochemical staining for HIF-1α was performed on 82 OSCC specimens using a standard immunoperoxidase technique. The expression of HIF-1α was correlated with poor disease-specific survival for OSCC patients. Patients with negatively or weakly HIF-1α–expressing tumors had a survival rate of 80%, whereas the survival decreased to only 33.6% in case of moderate or strong expression. In multivariate Cox regression analysis, we found a 3.5-fold increased risk of tumor-related death when HIF-1α was strongly expressed (p=0.016) compared to negative or weak expression of HIF-1α. We suggest HIF-1α is an independent prognostic marker in OSCC. Immunohistochemical detection of HIF-1α appears to be useful in the diagnosis of OSCC and to provide prognostic information in addition to TNM stage and histological grade.

scholarly journals Mutant collagen COL11A1 enhances cancerous invasion

Oncogene ◽  
2021 ◽  
Author(s):  
Carolyn S. Lee ◽  
Zurab Siprashvili ◽  
Angela Mah ◽  
Tomas Bencomo ◽  
Lara E. Elcavage ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Squamous Cell Carcinomas ◽  
Basement Membranes ◽  
The Body ◽  
Β1 Integrin ◽  
Wild Type ◽  
Collagen Genes ◽  
Helical Region

AbstractCollagens are the most abundant proteins in the body and comprise the basement membranes and stroma through which cancerous invasion occurs; however, a pro-neoplastic function for mutant collagens is undefined. Here we identify COL11A1 mutations in 66 of 100 cutaneous squamous cell carcinomas (cSCCs), the second most common U.S. cancer, concentrated in a triple helical region known to produce trans-dominant collagens. Analysis of COL11A1 and other collagen genes found that they are mutated across common epithelial malignancies. Knockout of mutant COL11A1 impairs cSCC tumorigenesis in vivo. Compared to otherwise genetically identical COL11A1 wild-type tissue, gene-edited mutant COL11A1 skin is characterized by induction of β1 integrin targets and accelerated neoplastic invasion. In mosaic tissue, mutant COL11A1 cells enhanced invasion by neighboring wild-type cells. These results suggest that specific collagens are commonly mutated in cancer and that mutant collagens may accelerate this process.

scholarly journals Increased lysophosphatidylcholine acyltransferase 1 expression is unrelated to prognosis of esophageal cancer patients

2021 ◽  
Author(s):  
Eugen Bellon ◽  
Katharina Grupp ◽  
Tarik Ghadban ◽  
Michael Tachezy ◽  
Kai Bachmann ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Cancer Patients ◽  
Tissue Microarray ◽  
Squamous Cell ◽  
High Intensity ◽  
Prognostic Biomarker ◽  
Squamous Cell Carcinomas ◽  
Tumor Grading ◽  
Esophageal Tissue

Abstract Introduction Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has repeatedly been suggested to be associated with tumorigenesis. To evaluate the role of LPCAT1 in esophageal cancer, LPCAT1 immunostaining was analyzed on a tissue microarray containing samples from esophageal cancer patients. Results In benign esophageal tissue, LPCAT1 staining was detectable in low intensities. LPCAT1 staining was increased in malignant as compared to benign esophageal tissue and was found in high intensity in 26.4% of 288 interpretable esophageal adenocarcinomas (EACs) and in 23.2% of 211 squamous cell carcinomas (ESCCs). Increased LPCAT1 staining was linked to undifferentiated tumor grading in both subtypes of EACs and ESCCs (p = 0.0273 and p = 0.0085). Conclusion However, LPCAT1 was not associated with prognosis of EAC and ESCC patients (p = 0.6838 and p = 0.4695) and thus cannot be considered a prognostic biomarker in esophageal cancers.

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