Tumor Development
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2021 ◽  
Vivian S Park ◽  
Meijuan JS Sun ◽  
Wesley D Frey ◽  
Leonard G Williams ◽  
Karl P Hodel ◽  

Mutations in the exonuclease domain of POLE are associated with tumors harboring very high mutation burdens. The mechanisms linking this significant mutation accumulation and tumor development remain poorly understood. Pole+/P286R;Trp53+/- mice showed accelerated cancer mortality compared to Pole+/P286R;Trp53+/+ mice. Cells from Pole+/P286R mice showed increased p53 activation, and subsequent loss of p53 permitted rapid growth, implicating canonical p53 loss of heterozygosity in POLE mutant tumor growth. Somewhat surprisingly, however, p53 status had no effect on tumor mutation burden or single base substitution signatures in POLE mutant tumors from mice or humans. Pten has important roles in maintaining genome stability. We find that PTEN mutations are highly enriched in human POLE mutant tumors, including many in POLE signature contexts. One such signature mutation, PTEN-F341V, was previously shown in a mouse model to specifically decrease nuclear Pten and lead to increased DNA damage. We found tumors in Pole+/P286R mice that spontaneously acquired PtenF341V mutations and were associated with significantly reduced nuclear Pten and elevated DNA damage. Taken together with recent published work, our results support the idea that POLE-mediated hypermutagenesis is necessary, but not entirely sufficient, for tumorigenesis. Disabling surveillance of nuclear DNA damage is a likely sufficient factor.

2021 ◽  
Vol 12 ◽  
Ran Wei ◽  
Shuofeng Li ◽  
Guanhua Yu ◽  
Xu Guan ◽  
Hengchang Liu ◽  

Background: Colon cancer (CC) remains one of the most common malignancies with a poor prognosis. Pyroptosis, referred to as cellular inflammatory necrosis, is thought to influence tumor development. However, the potential effects of pyroptosis-related regulators (PRRs) on the CC immune microenvironment remain unknown.Methods: In this study, 27 PRRs reported in the previous study were used to cluster the 1,334 CC samples into three pyroptosis-related molecular patterns. Through subtype pattern differential analysis and structure network mining using Weighted Gene Co-expression Network Analysis (WGCNA), 854 signature genes associated with the PRRs were discovered. Further LASSO-penalized Cox regression of these genes established an eight-gene assessment model for predicting prognosis.Results: The CC patients were subtyped based on three distinct pyroptosis-related molecular patterns. These pyroptosis-related patterns were correlated with different clinical outcomes and immune cell infiltration characteristics in the tumor microenvironment. The pyroptosis-related eight-signature model was established and used to assess the prognosis of CC patients with medium-to-high accuracy by employing the risk scores, which was named “PRM-scores.” Greater inflammatory cell infiltration was observed in tumors with low PRM-scores, indicating a potential benefit of immunotherapy in these patients.Conclusions: This study suggests that PRRs have a significant effect on the tumor immune microenvironment and tumor development. Evaluating the pyroptosis-related patterns and related models will promote our understanding of immune cell infiltration characteristics in the tumor microenvironment and provide a theoretical basis for future research targeting pyroptosis in cancer.

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1438
Wei-Lun Tsai ◽  
Chih-Yang Wang ◽  
Yu-Cheng Lee ◽  
Wan-Chun Tang ◽  
Gangga Anuraga ◽  

The development and progression of colorectal cancer (CRC) involve changes in genetic and epigenetic levels of oncogenes and/or tumor suppressors. In spite of advances in understanding of the molecular mechanisms involved in CRC, the overall survival rate of CRC still remains relatively low. Thus, more research is needed to discover and investigate effective biomarkers and targets for diagnosing and treating CRC. The roles of long non-coding RNAs (lncRNAs) participating in various aspects of cell biology have been investigated and potentially contribute to tumor development. Our recent study also showed that CRNDE was among the top 20 upregulated genes in CRC clinical tissues compared to normal colorectal tissues by analyzing a Gene Expression Omnibus (GEO) dataset (GSE21815). Although CRNDE is widely reported to be associated with different types of cancer, most studies of CRNDE were limited to examining regulation of its transcription levels, and in-depth mechanistic research is lacking. In the present study, CRNDE was found to be significantly upregulated in CRC patients at an advanced TNM stage, and its high expression was correlated with poor outcomes of CRC patients. In addition, we found that knocking down CRNDE could reduce lipid accumulation through the miR-29b-3p/ANGPTL4 axis and consequently induce autophagy of CRC cells.

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5040
Maja Sabol ◽  
Jean Calleja-Agius ◽  
Riccardo Di Di Fiore ◽  
Sherif Suleiman ◽  
Sureyya Ozcan ◽  

Rare ovarian cancers (ROCs) are OCs with an annual incidence of fewer than 6 cases per 100,000 women. They affect women of all ages, but due to their low incidence and the potential clinical inexperience in management, there can be a delay in diagnosis, leading to a poor prognosis. The underlying causes for these tumors are varied, but generally, the tumors arise due to alterations in gene/protein expression in cellular processes that regulate normal proliferation and its checkpoints. Dysregulation of the cellular processes that lead to cancer includes gene mutations, epimutations, non-coding RNA (ncRNA) regulation, posttranscriptional and posttranslational modifications. Long non-coding RNA (lncRNA) are defined as transcribed RNA molecules, more than 200 nucleotides in length which are not translated into proteins. They regulate gene expression through several mechanisms and therefore add another level of complexity to the regulatory mechanisms affecting tumor development. Since few studies have been performed on ROCs, in this review we summarize the mechanisms of action of lncRNA in OC, with an emphasis on ROCs.

2021 ◽  
Yan Mei ◽  
Jing Wang ◽  
Jia-Bin Lu ◽  
Guan-Ming Lu ◽  
Li-Xia Peng ◽  

Abstract Background: Dietary fat absorption involves the re-esterification of digested triacylglycerol in the enterocytes, it is a biological process catalyzed by monoacylglycerol O-acyltransferase 2 (MOGAT2, aka MGAT2), which is highly expressed in the small intestine. A previous study showed that the loss of the Mogat2 gene can prevent high-fat diet-induced obesity in mice. Obesity is associated with an increased risk of several types of cancer including postmenopausal breast cancer.Methods: We collected 147 patients with triple negative breast adenocarcinoma to explore the relationship between the expression of MOGAT2 and patient overall survival. And we generated a Mogat2-deficient mouse mammary tumor model by crossing Mogat2-deficient mice with MMTV-PyMT mice to examine the effect of losing MOGAT2 in vivo.Results: Our founding suggest that obesity was induced by a relatively high-fat diet (37% of calories from fat) in the mice with or without Mogat2 knockout. Mammary tumor development was deteriorated by a relatively high-fat diet regardless of Mogat2 deficiency. As a compensation mechanism, upregulation of diacylglycerol O-acyltransferases 1 and 2 (Dgat1 and Dgat2) in the Mogat2 deficient mice was found. Conclusions: Elevated expression of MOGAT2 in triple negative breast adenocarcinoma predicts poorer patient overall survival. With the compensation of Dgat1 and Dgat2, Mogat2 deficiency alone cannot prevent fat diet-induced obesity, nor prevent mammary tumor development in a mouse model.

2021 ◽  
Vol 7 (1) ◽  
Xinbao Zhang ◽  
Yuting Li ◽  
Junxiang Ji ◽  
Xin Wang ◽  
Meng Zhang ◽  

AbstractMany self-renewal-promoting factors of embryonic stem cells (ESCs) have been implicated in carcinogenesis, while little known about the genes that direct ESCs exit from pluripotency and regulate tumor development. Here, we show that the transcripts of Gadd45 family genes, including Gadd45a, Gadd45b, and Gadd45g, are gradually increased upon mouse ESC differentiation. Upregulation of Gadd45 members decreases cell proliferation and induces endodermal and trophectodermal lineages. In contrast, knockdown of Gadd45 genes can delay mouse ESC differentiation. Mechanistic studies reveal that Gadd45g activates MAPK signaling by increasing expression levels of the positive modulators of this pathway, such as Csf1r, Igf2, and Fgfr3. Therefore, inhibition of MAPK signaling with a MEK specific inhibitor is capable of eliminating the differentiation phenotype caused by Gadd45g upregulation. Meanwhile, GADD45G functions as a suppressor in human breast cancers. Enforced expression of GADD45G significantly inhibits tumor formation and breast cancer metastasis in mice through limitation of the propagation and invasion of breast cancer cells. These results not only expand our understanding of the regulatory network of ESCs, but also help people better treatment of cancers by manipulating the prodifferentiation candidates.

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2621
Travis C. Salzillo ◽  
Vimbai Mawoneke ◽  
Joseph Weygand ◽  
Akaanksh Shetty ◽  
Joy Gumin ◽  

Rapid diagnosis and therapeutic monitoring of aggressive diseases such as glioblastoma can improve patient survival by providing physicians the time to optimally deliver treatment. This research tested whether metabolic imaging with hyperpolarized MRI could detect changes in tumor progression faster than conventional anatomic MRI in patient-derived glioblastoma murine models. To capture the dynamic nature of cancer metabolism, hyperpolarized MRI, NMR spectroscopy, and immunohistochemistry were performed at several time-points during tumor development, regression, and recurrence. Hyperpolarized MRI detected significant changes of metabolism throughout tumor progression whereas conventional MRI was less sensitive. This was accompanied by aberrations in amino acid and phospholipid lipid metabolism and MCT1 expression. Hyperpolarized MRI can help address clinical challenges such as identifying malignant disease prior to aggressive growth, differentiating pseudoprogression from true progression, and predicting relapse. The individual evolution of these metabolic assays as well as their correlations with one another provides context for further academic research.

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4927
Mahmoud Aghaei ◽  
Ahmad Nasimian ◽  
Marveh Rahmati ◽  
Philip Kawalec ◽  
Filip Machaj ◽  

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and is associated with a poor prognosis in patients presenting with recurrent or metastatic disease. The unfolded protein response (UPR) plays pivotal roles in tumor development and resistance to therapy, including RMS. Methods: In this study, we used immunohistochemistry and a tissue microarray (TMA) on human RMS and normal skeletal muscle to evaluate the expression of key UPR proteins (GRP78/BiP, IRE1α and cytosolic/nuclear XBP1 (spliced XBP1-sXBP1)) in the four main RMS subtypes: alveolar (ARMS), embryonal (ERMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS. We also investigated the correlation of these proteins with the risk of RMS and several clinicopathological indices, such as lymph node involvement, distant metastasis, tumor stage and tumor scores. Results: Our results revealed that the expression of BiP, sXBP1, and IRE1α, but not cytosolic XBP1, are significantly associated with RMS (BiP and sXBP1 p-value = 0.0001, IRE1 p-value = 0.001) in all of the studied types of RMS tumors (n = 192) compared to normal skeletal muscle tissues (n = 16). In addition, significant correlations of BiP with the lymph node score (p = 0.05), and of IRE1α (p value = 0.004), cytosolic XBP1 (p = 0.001) and sXBP1 (p value = 0.001) with the stage score were observed. At the subtype level, BiP and sXBP1 expression were significantly associated with all subtypes of RMS, whereas IRE1α was associated with ARMS, PRMS and ERMS, and cytosolic XBP1 expression was associated with ARMS and SRMS. Importantly, the expression levels of IRE1α and sXBP1 were more pronounced in ARMS than in any of the other subtypes. The results also showed correlations of BiP with the lymph node score in ARMS (p value = 0.05), and of sXBP1 with the tumor score in PRMS (p value = 0.002). Conclusions: In summary, this study demonstrates that the overall UPR is upregulated and, more specifically, that the IRE1/sXBP1 axis is active in RMS. The subtype and stage-specific dependency on the UPR machinery in RMS may open new avenues for the development of novel targeted therapeutic strategies and the identification of specific tumor markers in this rare but deadly childhood and young-adult disease.

Ebrahim Balandeh ◽  
Kimia Mohammadshafie ◽  
Yaser Mahmoudi ◽  
Mohammad Hossein Pourhanifeh ◽  
Ali Rajabi ◽  

One of the significant hallmarks of cancer is angiogenesis. It has a crucial function in tumor development and metastasis. Thus, angiogenesis has become one of the most exciting targets for drug development in cancer treatment. Here we discuss the regulatory effects on angiogenesis in glioblastoma (GBM) of non-coding RNAs (ncRNAs), including long ncRNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA). These ncRNAs may function in trans or cis forms and modify gene transcription by various mechanisms, including epigenetics. NcRNAs may also serve as crucial regulators of angiogenesis-inducing molecules. These molecules include, metalloproteinases, cytokines, several growth factors (platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor, hypoxia-inducible factor-1, and epidermal growth factor), phosphoinositide 3-kinase, mitogen-activated protein kinase, and transforming growth factor signaling pathways.

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4807
Miguel Ruiz de la Cruz ◽  
Aldo Hugo de la Cruz Montoya ◽  
Ernesto Arturo Rojas Jiménez ◽  
Héctor Martínez Gregorio ◽  
Clara Estela Díaz Velásquez ◽  

Epigenetics affects gene expression and contributes to disease development by alterations known as epimutations. Hypermethylation that results in transcriptional silencing of tumor suppressor genes has been described in patients with hereditary cancers and without pathogenic variants in the coding region of cancer susceptibility genes. Although somatic promoter hypermethylation of these genes can occur in later stages of the carcinogenic process, constitutional methylation can be a crucial event during the first steps of tumorigenesis, accelerating tumor development. Primary epimutations originate independently of changes in the DNA sequence, while secondary epimutations are a consequence of a mutation in a cis or trans-acting factor. Secondary epimutations have a genetic basis in cis of the promoter regions of genes involved in familial cancers. This highlights epimutations as a novel carcinogenic mechanism whose contribution to human diseases is underestimated by the scarcity of the variants described. In this review, we provide an overview of secondary epimutations and present evidence of their impact on cancer. We propose the necessity for genetic screening of loci associated with secondary epimutations in familial cancer as part of prevention programs to improve molecular diagnosis, secondary prevention, and reduce the mortality of these diseases.

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