scholarly journals The Mechanobiome: A Goldmine for Cancer Therapeutics

2020 ◽  
Author(s):  
Eleana Parajón ◽  
Alexandra Surcel ◽  
Douglas N. Robinson
Keyword(s):  
Cancer Progression ◽  
Expression Patterns ◽  
Cancer Therapeutics ◽  
Cellular Systems ◽  
Cancer Drug ◽  
Altered Expression ◽  
Mechanical Adaptation ◽  
Gene And Protein Expression ◽  
Wide Range ◽  
Cancer Types

Cancer progression is dependent on heightened mechanical adaptation, both for the cells' ability to change shape and to interact with varying mechanical environments. This type of adaptation is dependent on mechanoresponsive proteins that sense and respond to mechanical stress, as well as their regulators. Mechanoresponsive proteins are part of the mechanobiome, which is the larger network that constitutes the cell's mechanical systems that are also highly integrated with many other cellular systems, such as gene expression, metabolism, and signaling. Despite the altered expression patterns of key mechanobiome proteins across many different cancer types, pharmaceutical targeting of these proteins has been overlooked. Here we review the biochemistry of key mechanoresponsive proteins, specifically nonmuscle myosin II, α-actinins, and filamins, as well as the partnering proteins 14-3-3 and CLP36. We also examined a wide range of data sets to assess how gene and protein expression levels of these proteins are altered across many different cancer types. Finally, we determined the potential of targeting these proteins to mitigate invasion or metastasis and suggest that the mechanobiome is a goldmine of opportunity for anti-cancer drug discovery and development.

scholarly journals Identification of Key Differentially Expressed MicroRNAs in Cancer Patients Through Pan-cancer Analysis

2018 ◽  
Author(s):  
Yu Hu ◽  
Hayley Dingerdissen ◽  
Samir Gupta ◽  
Robel Kahsay ◽  
Vijay Shanker ◽  
...  
Keyword(s):  
Differential Expression ◽  
Cancer Progression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Differential Expression Analysis ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Literature Mining ◽  
Wide Range ◽  
Cancer Types

AbstractA number of microRNAs (miRNAs) functioning in gene silencing have been associated with cancer progression. However, common expression patterns of abnormally expressed miRNAs and their potential roles in multiple cancer types have not yet been evaluated. To minimize the difference of patients, we collected miRNA sequencing data of 575 patients with tumor and adjacent non-tumorous tissues from 14 cancer types from The Cancer Genome Atlas (TCGA), and performed differential expression analysis using DESeq2 and edgeR. The results showed that cancer types can be grouped based on the distribution of miRNAs with different expression patterns. We found 81 significantly differentially expressed miRNAs (SDEmiRNAs) unique to one of the 14 cancers may affect patient survival rate, and 21 key SDEmiRNAs (nine overexpressed and 12 under-expressed) associated with at least eight cancers and enriched in more than 60% of patients per cancer, including four newly identified SDEmiRNAs (hsa-mir-4746, hsa-mir-3648, hsa-mir-3687, and hsa-mir-1269a). The downstream effect of these 21 SDEmiRNAs on cellular functions was evaluated through enrichment and pathway analysis of 7,186 protein-coding gene targets from literature mining with known differential expression profiles in cancers. It enables identification of their functional similarity in cell proliferation control across a wide range of cancers and to build common regulatory networks over cancer-related pathways. This is validated by construction of a regulatory network in PI3K pathway. This study provides evidence of the value of further analysis on SDEmiRNAs as potential biomarkers and therapeutic targets for cancer diagnosis and treatment.

scholarly journals Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 433
Author(s):  
Bijesh George ◽  
P. Mukundan Pillai ◽  
Aswathy Mary Paul ◽  
Revikumar Amjesh ◽  
Kim Leitzel ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Survival Duration ◽  
Cancer Drug ◽  
Targeted Therapeutics ◽  
Cellular Targets ◽  
Human Cancer Cells ◽  
Cancer Types

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

scholarly journals Systematic identification of non-coding somatic single nucleotide variants associated with altered transcription and DNA methylation in adult and pediatric cancers

NAR Cancer ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Fengju Chen ◽  
Yiqun Zhang ◽  
Chad J Creighton
Keyword(s):  
Dna Methylation ◽  
Brain Tumor ◽  
Low Grade ◽  
Single Nucleotide Variants ◽  
Multiple Cancer ◽  
Single Nucleotide ◽  
Altered Expression ◽  
Wide Range ◽  
Mutational Hotspots ◽  
Cancer Types

Abstract Whole-genome sequencing combined with transcriptomics can reveal impactful non-coding single nucleotide variants (SNVs) in cancer. Here, we developed an integrative analytical approach that, as a first step, identifies genes altered in expression or DNA methylation in association with nearby somatic SNVs, in contrast to alternative approaches that first identify mutational hotspots. Using genomic datasets from the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium and the Children's Brain Tumor Tissue Consortium (CBTTC), we identified hundreds of genes and associated CpG islands for which the nearby presence of a non-coding somatic SNV recurrently associated with altered expression or DNA methylation, respectively. Genomic regions upstream or downstream of genes, gene introns and gene untranslated regions were all involved. The PCAWG adult cancer cohort yielded different significant SNV-expression associations from the CBTTC pediatric brain tumor cohort. The SNV-expression associations involved a wide range of cancer types and histologies, as well as potential gain or loss of transcription factor binding sites. Notable genes with SNV-associated increased expression include TERT, COPS3, POLE2 and HDAC2—involving multiple cancer types—MYC, BCL2, PIM1 and IGLL5—involving lymphomas—and CYHR1—involving pediatric low-grade gliomas. Non-coding somatic SNVs show a major role in shaping the cancer transcriptome, not limited to mutational hotspots.

scholarly journals Cellular Fitness Phenotypes of Cancer Target Genes in Cancer Therapeutics

2019 ◽  
Author(s):  
Bijesh George ◽  
P. Mukundan Pillai ◽  
Aswathy Mary Paul ◽  
Kim Leitzel ◽  
Suhail M. Ali ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Survival Duration ◽  
Cancer Drug ◽  
Cellular Targets ◽  
Human Cancer Cells ◽  
Cancer Types ◽  
Approved Drugs

AbstractTo define the growing significance of cellular targets of targeted cancer drugs, we examined the fitness dependency of cancer drug targets across human cancer cells in a CRISPR-Cas9 fitness screening dataset wherein cellular genes were selectively knocked out before assaying for their fitness dependency in cancer cell lines representing 19 cancer types. We observed that the deletion of 35 out of 47 fitness targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting these molecules were approved. This raised the possibility of undesirable off-target effects of these drugs in such cancers. Additionally, our analysis recognized 43 drug targets which were fitness genes observed in several cancer types as candidate targets for repurposing approved oncology drugs in cancer types in which these drugs were not approved. For example, we found the widespread upregulation and fitness dependency of the components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these targets and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which these drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended drug targets are not fitness genes. The study also offers a rationale for repurposing approved oncology drugs for cancer types that have significant fitness dependency on cellular targets of such approved drugs.

Quest of EMT and CSC

2019 ◽  
Author(s):  
Shihori Tanabe
Keyword(s):  
Drug Resistance ◽  
Stem Cell ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Therapeutics ◽  
Cancer Drug ◽  
Phenotypic Change ◽  
Mesenchymal Transition ◽  
Cancer Drug Resistance ◽  
The Relationship

Epithelial-mesenchymal transition (EMT), an important phenotypic change from epithelial to mesenchymal like cells, has the increasing impact for cancer progression in terms of the involvement in cancer stem cell (CSC). The EMT-featured cells and CSCs are important factors for the acquisition of cancer drug resistance. The understanding of EMT program activation is important for targeting CSCs in cancer therapy. The relationship between EMT and CSC in cancer therapeutics is focused in the editorial.

scholarly journals The role of MT1-MMP in the progression and metastasis of osteosarcoma

2022 ◽  
Author(s):  
Hannah L. M. Spencer ◽  
Steven D. Shnyder ◽  
Paul M. Loadman ◽  
Robert A. Falconer
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Clinical Samples ◽  
Gene And Protein Expression ◽  
Cancer Types ◽  
Membrane Type

The dysregulation of Membrane - type 1 matrix metalloproteinase (MT1-MMP) has been extensively studied in numerous cancer types, and plays key roles in angiogenesis, cancer progression, and metastasis. MT1-MMP is a predictor of poor prognosis in osteosarcoma (OS), yet the molecular mechanisms of disease progression are unclear. This review provides a summary of the literature relating to the gene and protein expression of MT1-MMP (MMP-14) in OS clinical samples, evaluates the expression in cell lines and experimental models, and analyses its potential role in the progression and metastasis of OS. In addition, the therapeutic potential of MT1-MMP as a drug target has been assessed. Due to the biological complexity of MMPs, inhibition has proven to be challenging. However, exploiting the expression and proteolytic capacity of MT1-MMP could open new avenues in the search for novel, safer and selective drugs for use in OS.

scholarly journals Aberrant alternative splicing in breast cancer

2019 ◽  
Vol 11 (10) ◽  
pp. 920-929 ◽  
Author(s):  
Quan Yang ◽  
Jinyao Zhao ◽  
Wenjing Zhang ◽  
Dan Chen ◽  
Yang Wang
Keyword(s):  
Breast Cancer ◽  
Alternative Splicing ◽  
Cancer Progression ◽  
Gene Expression Regulation ◽  
Cancer Therapeutics ◽  
Cancer Drug ◽  
Splicing Factors ◽  
Cancer Drug Resistance ◽  
The Relationship

Abstract Alternative splicing is critical for human gene expression regulation, which plays a determined role in expanding the diversity of functional proteins. Importantly, alternative splicing is a hallmark of cancer and a potential target for cancer therapeutics. Based on the statistical data, breast cancer is one of the top leading causes of cancer-related deaths in women worldwide. Strikingly, alternative splicing is closely associated with breast cancer development. Here, we seek to provide a general review of the relationship between alternative splicing and breast cancer. We introduce the process of alternative splicing and its regulatory role in cancers. In addition, we highlight the functions of aberrant alternative splicing and mutations of splicing factors in breast cancer progression. Moreover, we discuss the role of alternative splicing in cancer drug resistance and the potential of being targets for cancer therapeutics.

scholarly journals Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

2021 ◽  
Vol 8 ◽  
Author(s):  
Vinodh Kannappan ◽  
Misha Ali ◽  
Benjamin Small ◽  
Gowtham Rajendran ◽  
Salena Elzhenni ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Molecular Targets ◽  
Cancer Therapeutics ◽  
New Drugs ◽  
Cancer Clinical Trials ◽  
Anticancer Efficacy ◽  
Wide Range

Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.

scholarly journals The Biomarker Potential of Caveolin-1 in Penile Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Andrej Panic ◽  
Henning Reis ◽  
Alina Wittka ◽  
Christopher Darr ◽  
Boris Hadaschik ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Penile Cancer ◽  
Expression Patterns ◽  
Human Papilloma Virus Infection ◽  
Tumor Stroma ◽  
Stromal Compartment ◽  
Altered Expression ◽  
Caveolin 1 ◽  
Clinicopathological Significance ◽  
Cav1 Expression

Various types of human cancers were characterized by an altered expression of epithelial or stromal caveolin-1 (CAV1). However, the clinical significance of CAV1 expression in penile cancer remains largely unknown. Here the expression patterns of CAV1 were analyzed in a retrospective cohort (n=43) of penile squamous cell carcinomas (SCC). Upon penile cancer progression, significantly increased CAV1-levels were determined within the malignant epithelium, whereas within the tumor stroma, namely the fibroblastic tumor compartment harboring activated and/or cancer associated fibroblasts, CAV1 levels significantly decline. Concerning the clinicopathological significance of CAV1 expression in penile cancer as well as respective epithelial-stromal CAV1 distributions, high expression within the tumor cells as well as low expression of CAV1 within the stromal compartment were correlated with decreased overall survival of penile cancer patients. Herein, CAV1 expressions and distributions at advanced penile cancer stages were independent of the immunohistochemically proven tumor protein p53 status. In contrast, less differentiated p16-positive tumor epithelia (indicative for human papilloma virus infection) were characterized by significantly decreased CAV1 levels. Conclusively, we provide further and new evidence that the characteristic shift in stromal‐epithelial CAV1 being functionally relevant to tumor progression even occurs in penile SCC.

scholarly journals Differential Transcriptomic Profiles in Canine Intestinal Organoids Following Lipopolysaccharide Stimulation

2022 ◽  
Author(s):  
Dipak K. Sahoo ◽  
Dana C. Borcherding ◽  
Lawrance Chandra ◽  
Albert E. Jergens ◽  
Todd Atherly ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cancer Progression ◽  
Intestinal Inflammation ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Signal Transduction Pathway ◽  
Glutathione Metabolism ◽  
Study Objective ◽  
Altered Expression ◽  
Chronic Intestinal Inflammation

Abstract Lipopolysaccharide (LPS) is associated with chronic intestinal inflammation and promotes intestinal cancer progression in the gut. While the interplay between LPS and intestinal immune cells has been well characterized, little is known about LPS and intestinal epithelium interactions. In this study, we explored the differential effect of LPS on proliferation and the transcriptome in 3D enteroids/colonoids obtained from dogs with naturally occurring gastrointestinal (GI) diseases, such as Inflammatory Bowel Disease (IBD) and GI mast cell tumor. The study objective was to analyze LPS-induced modulation of signaling pathways involving the intestinal epithelia and critical to colorectal cancer development in the context of IBD or a tumor microenvironment. While LPS incubation resulted in a pro-cancer gene expression pattern and stimulated proliferation of IBD enteroids and colonoids, down-regulation of several cancer-associated genes like CRYZL1, Gpatch4, SLC7A1, ATP13A2, and ZNF358 was also observed in tumor enteroids. Genes participating in porphyrin metabolism (CP), thiamine and purine metabolism (TAP2, EEF1A1), arachidonic acid, and glutathione metabolism (GPX1) exhibited a similar pattern of altered expression between IBD enteroids and IBD colonoids following LPS stimulation. In contrast, genes involved in anion transport, transcription and translation, apoptotic processes, and regulation of adaptive immune responses showed opposite expression patterns between IBD enteroids and colonoids following LPS treatment. In brief, the cross-talk between LPS/TLR4 signal transduction pathway and several metabolic pathways, such as fatty acid degradation and biosynthesis, and purine, thiamine, arachidonic acid, and glutathione metabolism, may be important in driving chronic intestinal inflammation and intestinal carcinogenesis.

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