scholarly journals Diversity and Biology of Cancer-Associated Fibroblasts

2021 ◽  
Vol 101 (1) ◽  
pp. 147-176 ◽  
Author(s):  
Giulia Biffi ◽  
David A. Tuveson
Keyword(s):  
Cancer Cell ◽  
Therapy Resistance ◽  
The Body ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblasts ◽  
Anti Cancer ◽  
Cancer Cell Survival ◽  
Epithelial Compartment ◽  
Cancer Types ◽  
Immune Exclusion

Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.

scholarly journals Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

2020 ◽  
Author(s):  
Wen Jia ◽  
Shubham Tripathi ◽  
Priyanka Chakraborty ◽  
Adithya Chedere ◽  
Annapoorni Rangarajan ◽  
...  
Keyword(s):  
Cell Division ◽  
Epithelial Mesenchymal Transition ◽  
Experimental Studies ◽  
Therapy Resistance ◽  
Cancer Therapies ◽  
Mesenchymal Transition ◽  
Anti Cancer ◽  
Molecular Determinants ◽  
Cancer Types ◽  
Mesenchymal Epithelial Transition

AbstractEpithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

scholarly journals Replication gaps are a cancer vulnerability counteracted by translesion synthesis

2019 ◽  
Author(s):  
Sumeet Nayak ◽  
Jennifer A. Calvo ◽  
Ke Cong ◽  
Emily Berthiaume ◽  
Jessica Jackson ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dna Damage ◽  
Stress Response ◽  
Cancer Cell ◽  
Replication Fork ◽  
Translesion Synthesis ◽  
Cancer Therapies ◽  
Fiber Analysis ◽  
Molecule Inhibitor ◽  
Anti Cancer

SUMMARYThe replication stress response which serves as an anti-cancer barrier is activated not only by DNA damage and replication obstacles, but also oncogenes, mystifying how cancer evolves. Here, we identify that oncogene expression, similar to cancer therapies, induces single stranded DNA (ssDNA) gaps that reduce cell fitness, unless suppressed by translesion synthesis (TLS). DNA fiber analysis and electron microscopy reveal that TLS restricts replication fork slowing, reversal, and fork degradation without inducing replication fork gaps. Evidence that TLS gap suppression is fundamental to cancer, a small molecule inhibitor targeting the TLS factor, REV1, not only disrupts DNA replication and cancer cell fitness, but also synergizes with gap-inducing therapies. This work illuminates that gap suppression during replication is critical for cancer cell fitness and therefore a targetable vulnerability.

scholarly journals New Insights into Curcumin- and Resveratrol-Mediated Anti-Cancer Effects

2021 ◽  
Vol 14 (11) ◽  
pp. 1068
Author(s):  
Andrea Arena ◽  
Maria Anele Romeo ◽  
Rossella Benedetti ◽  
Laura Masuelli ◽  
Roberto Bei ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cancer Cell ◽  
Cytotoxic Effect ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Cytotoxic Effects ◽  
Anti Cancer ◽  
Cancer Cell Survival ◽  
Anti Oxidant ◽  
Her 2

Curcumin and resveratrol are bioactive natural compounds displaying anti-inflammatory, anti-oxidant and anti-cancer properties. In this study, we compared the cytotoxic effects of these molecules and the molecular mechanisms involved against Her-2/neu-positive breast and salivary cancer cell lines. We found that both curcumin and resveratrol were efficient in reducing cancer cell survival and that they differently affected autophagy, ROS and activation of the PI3K/AKT/mTOR pathway. Moreover, we found that resveratrol and curcumin in combination exerted a stronger cytotoxic effect in correlation with the induction of a stronger ER stress and the upregulation of pro-death UPR molecule CHOP. This effect also correlated with the induction of pro-survival autophagy by curcumin and its inhibition by resveratrol. In conclusion, this study unveils new molecular mechanisms underlying the anti-cancer effects of resveratrol, curcumin and their combination, which can help to design new therapeutic strategies based on the use of these polyphenols.

scholarly journals Why is cancer not more common? A changing microenvironment may help to explain why, and suggests strategies for anti-cancer therapy

2018 ◽  
Author(s):  
Xiaowei Jiang ◽  
Ian P.M. Tomlinson
Keyword(s):  
Cancer Cell ◽  
Cancer Biology ◽  
Treatment Strategies ◽  
Tumour Microenvironment ◽  
The Body ◽  
Driver Mutations ◽  
Cell Populations ◽  
Cancer Evolution ◽  
Cancer Driver ◽  
Anti Cancer

AbstractOne of the great unsolved puzzles in cancer biology is not why cancers occur, but rather, explaining why so few cancers occur compared with the theoretical number that could occur given the number of progenitor cells in the body and the normal mutation rate. We hypothesised that a contributory explanation is that the tumour microenvironment (TME) is not fixed, and that this could impair the ability of neoplastic cells to retain a high enough fitness to become a cancer. The TME has implicitly been assumed to be static in most cancer evolution models, and we therefore developed a mathematical model of spatial cancer evolution assuming that the TME, and thus the optimum cancer phenotype, change over time. Based on simulations, we show how cancer cell populations adapt to diverse changing TME conditions and fitness landscapes. Compared with static TMEs which generate neutral dynamics, changing TMEs lead to complex adaptations with spatio-temporal heterogeneity involving variable sub-clonal fitness, mixing, competition and phylogeny patterns. In many cases, cancer cell populations fail to grow or undergo spontaneous regression, and even extinction. Our analyses predict that cancer evolution in a changing TME is challenging, and can help to explain why cancer is neither inevitable nor as common as expected. Should cancer driver mutations with effects dependent of the TME exist, they are likely to be selected. Anti-cancer prevention and treatment strategies based on changing the TME are feasible and potentially effective.

scholarly journals Why is cancer not more common? A changing microenvironment may help to explain why, and suggests strategies for anti-cancer therapy

Open Biology ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 190297
Author(s):  
Xiaowei Jiang ◽  
Ian P. M. Tomlinson
Keyword(s):  
Cancer Cell ◽  
Cancer Biology ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Tumour Microenvironment ◽  
The Body ◽  
Driver Mutations ◽  
Cell Populations ◽  
Cancer Evolution ◽  
Anti Cancer

One of the great unsolved puzzles in cancer biology is not why cancers occur, but rather explaining why so few cancers occur compared with the theoretical number that could occur, given the number of progenitor cells in the body and the normal mutation rate. We hypothesized that a contributory explanation is that the tumour microenvironment (TME) is not fixed due to factors such as immune cell infiltration, and that this could impair the ability of neoplastic cells to retain a high enough fitness to become a cancer. The TME has implicitly been assumed to be static in most cancer evolution models, and we therefore developed a mathematical model of spatial cancer evolution assuming that the TME, and thus the optimum cancer phenotype, changes over time. Based on simulations, we show how cancer cell populations adapt to diverse changing TME conditions and fitness landscapes. Compared with static TMEs, which generate neutral dynamics, changing TMEs lead to complex adaptations with characteristic spatio-temporal heterogeneity involving variable fitness effects of driver mutations, subclonal mixing, subclonal competition and phylogeny patterns. In many cases, cancer cell populations fail to grow or undergo spontaneous regression, and even extinction. Our analyses predict that cancer evolution in a changing TME is challenging, and can help to explain why cancer is neither inevitable nor as common as expected. Should cancer driver mutations with effects dependent of the TME exist, they are likely to be selected. Anti-cancer prevention and treatment strategies based on changing the TME are feasible and potentially effective.

scholarly journals P06.04 Transcriptome-wide network analysis predicts the role of lactate dehydrogenase C in breast cancer cell survival and immune dysfunction

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A20.2-A21
Author(s):  
A Naik ◽  
J Decock
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Immune Dysfunction ◽  
Anti Cancer ◽  
Damage Response ◽  
Cancer Cell Survival ◽  
Breast Cancer Cohort ◽  
Lactate Dehydrogenase C ◽  
Cell Transcriptome

BackgroundCancer testis antigens (CTAs) are lucrative anti-cancer targets given their restricted expression patterns and known roles as mediators of cancer hallmarks, including cancer metabolism, proliferation, survival, and cell motility. Lactate dehydrogenase C (LDHC) is a CTA with upregulated expression in poor prognosis subtypes of breast cancer, however its tumorigenic role is less understood. We recently reported that silencing LDHC reduces breast cancer cell survival through a dysregulated DNA damage response, thus highlighting its potential as an anti-cancer target with limited off-target effects. This study aimed to explore the changes in the transcriptome of breast cancer cells and immune-related mediators upon in vitro LDHC targeting.Materials and MethodsWe silenced LDHC expression in breast cancer cell lines and investigated the downstream effects on the tumor cell transcriptome. Differentially expressed genes were subjected to regulatory network analyses. We further assessed the secretory profile of cytokines and immune checkpoint expression in LDHC-silenced cells and used the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm to determine the effect of the interaction between LDHC expression and cytotoxic T lymphocyte (CTL) infiltration in the METABRIC breast cancer cohort.ResultsNetwork analysis to investigate the effects of silencing LDHC on the tumor cell transcriptome identified 47 up- and 55 down-regulated transcripts (2.0-fold change, adj p<0.05). Differentially expressed genes in the LDHC-silenced cells were particularly enriched in canonical pathways regulating cell cycle checkpoint control, BRCA1-mediated DNA damage response and NF-kb signaling in response to infection. Upstream regulator analyses revealed the altered expression profile was associated with mTOR (p=1.27e-5, z=2.242) and CASP3 (p=3.2e-4, z=2.250) pathways, which in the presence of LDHC are predicted to activate TP53, Myc, NF-KB complex, STAT1/3, PRKC, CDK2, FOXO3 and HIF-1a while inhibiting SMAD3, PTEN, ATM, IL18 and BCL2. Consequentially, the observed network-wide changes on LDHC silencing are predicted to negatively influence cellular growth and proliferation, cell migration and cell infiltration. The LDHC-associated network indicated a higher-level regulation by miR378a-3p (p=1.4e-7, z=-3.117), affecting the downstream mechanistic in LDHC-expressing cells. Interestingly, the miR378a causal network also indicated inhibition of the immune response in LDHC-positive cells. TIDE analysis indicated that high expression of LDHC in the METABRIC Her2 breast cancer cohort (TIDE score=1.97, p=0.049), and to a lesser extent in triple negative breast cancer (TIDE score=0.466, p=0.642), decreases the beneficial effect between CTLs and overall survival observed in LDHC Low tumors. Concurrently, LDHC-silenced cells displayed a pro-inflammatory gene expression and cytokine profile and down-regulated the expression of PD-L1 and Gal-9 immune checkpoints.ConclusionsOur findings provide an indication of potential CTL dysfunction in breast tumors with high LDHC expression and suggests that therapeutic targeting of LDHC may inhibit tumor growth while releasing the anti-tumor immune response in breast cancer.Disclosure InformationA. Naik: None. J. Decock: None.

scholarly journals Involvement of Breast Cancer-Associated Fibroblasts in Tumor Development, Therapy Resistance and Evaluation of Potential Therapeutic Strategies

2018 ◽  
Vol 25 (29) ◽  
pp. 3414-3434 ◽  
Author(s):  
Maria Rosaria Ruocco ◽  
Angelica Avagliano ◽  
Giuseppina Granato ◽  
Valeria Imparato ◽  
Stefania Masone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Chemotherapy Resistance ◽  
Tumor Development ◽  
Therapy Resistance ◽  
Therapeutic Strategies ◽  
Activation Process ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancer Patients ◽  
Cancer Management

Breast cancer is the most common cancer in women, which incidence has increased in recent years. It is constituted by very heterogeneous tissue characterized by an abnormal microenvironment regulating tumor progression and providing evasion from cancer therapies. Breast cancer-associated fibroblasts (BCAFs) are the main cell type of breast cancer microenvironment and can represent up to 80% of the tumor mass. In particular, BCAFs induce cancer initiation, proliferation, invasion and metastasis by undergoing an activation process associated with the secretion of growth factors, cytokines, and paracrine interactions. Therapy resistance is the main cause of poor therapeutic results or even failure in breast cancer patients. Despite recent advances in breast cancer management, there is a need for new prognostic markers and novel agents for targeting key signalling pathways to either improve the efficacy of the current therapies, or reduce toxicity. In this view, BCAFs represent markers useful to clinical diagnosis, therapy, and prognosis of breast cancer. This review focuses on the role of BCAFs in cancer, and describes the processes of endocrine/chemotherapy resistance linked to BCAFs action. Moreover, it points to molecules and pathways regulating therapy resistance induced by BCAFs. Finally, potential therapeutic strategies targeting BCAFs and offering new tools in breast cancer therapy are highlighted.

scholarly journals Recent Advances and Implication of Bioengineered Nanomaterials in Cancer Theranostics

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 91
Author(s):  
Ayushi Rai ◽  
Saba Noor ◽  
Syed Ishraque Ahmad ◽  
Mohamed F. Alajmi ◽  
Afzal Hussain ◽  
...  
Keyword(s):  
Causes Of Death ◽  
High Surface ◽  
High Surface Area ◽  
Controlled Drug Release ◽  
Cancer Therapies ◽  
Infectious Agents ◽  
Anti Cancer ◽  
Common Causes ◽  
Cancer Types ◽  
Cancer Theranostics

Cancer is one of the most common causes of death and affects millions of lives every year. In addition to non-infectious carcinogens, infectious agents contribute significantly to increased incidence of several cancers. Several therapeutic techniques have been used for the treatment of such cancers. Recently, nanotechnology has emerged to advance the diagnosis, imaging, and therapeutics of various cancer types. Nanomaterials have multiple advantages over other materials due to their small size and high surface area, which allow retention and controlled drug release to improve the anti-cancer property. Most cancer therapies have been known to damage healthy cells due to poor specificity, which can be avoided by using nanosized particles. Nanomaterials can be combined with various types of biomaterials to make it less toxic and improve its biocompatibility. Based on these properties, several nanomaterials have been developed which possess excellent anti-cancer efficacy potential and improved diagnosis. This review presents the latest update on novel nanomaterials used to improve the diagnostic and therapeutic of pathogen-associated and non-pathogenic cancers. We further highlighted mechanistic insights into their mode of action, improved features, and limitations.

scholarly journals Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2337
Author(s):  
Adam Eckburg ◽  
Joshua Dein ◽  
Joseph Berei ◽  
Zachary Schrank ◽  
Neelu Puri
Keyword(s):  
Cancer Therapeutics ◽  
Telomerase Activity ◽  
Cancer Therapies ◽  
Human Telomerase Reverse Transcriptase ◽  
Conceptual Foundation ◽  
Telomerase Inhibitors ◽  
Current State ◽  
Anti Cancer ◽  
Cancer Types ◽  
Human Telomerase

Telomerase provides cancer cells with replicative immortality, and its overexpression serves as a near-universal marker of cancer. Anti-cancer therapeutics targeting telomerase have garnered interest as possible alternatives to chemotherapy and radiotherapy. Oligonucleotide-based therapies that inhibit telomerase through direct or indirect modulation of its subunits, human telomerase reverse transcriptase (hTERT) and human telomerase RNA gene (hTERC), are a unique and diverse subclass of telomerase inhibitors which hold clinical promise. MicroRNAs that play a role in the upregulation or downregulation of hTERT and respective progression or attenuation of cancer development have been effectively targeted to reduce telomerase activity in various cancer types. Tumor suppressor miRNAs, such as miRNA-512-5p, miRNA-138, and miRNA-128, and oncogenic miRNAs, such as miRNA-19b, miRNA-346, and miRNA-21, have displayed preclinical promise as potential hTERT-based therapeutic targets. Antisense oligonucleotides like GRN163L and T-oligos have also been shown to uniquely target the telomerase subunits and have become popular in the design of novel cancer therapies. Finally, studies suggest that G-quadruplex stabilizers, such as Telomestatin, preserve telomeric oligonucleotide architecture, thus inhibiting hTERC binding to the telomere. This review aims to provide an adept understanding of the conceptual foundation and current state of therapeutics utilizing oligonucleotides to target the telomerase subunits, including the advantages and drawbacks of each of these approaches.

scholarly journals Astaxanthin Reduces Stemness Markers in BT20 and T47D Breast Cancer Stem Cells by Inhibiting Expression of Pontin and Mutant p53

Marine Drugs ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. 577
Author(s):  
Yong Tae Ahn ◽  
Min Sung Kim ◽  
Youn Sook Kim ◽  
Won Gun An
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Cancer Cell Line ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Cancer Therapies ◽  
Anti Cancer

Astaxanthin (AST) is a product made from marine organisms that has been used as an anti-cancer supplement. It reduces pontin expression and induces apoptosis in SKBR3, a breast cancer cell line. Using Western blotting and qRT-PCR analyses, this study revealed that in the T47D and BT20 breast cancer cell lines, AST inhibits expression of pontin and mutp53, as well as the Oct4 and Nanog cancer stem cell (CSC) stemness genes. In addition, we explored the mechanism by which AST eradicates breast cancer cells using pontin siRNAs. Pontin knockdown by pontin siRNA reduced proliferation, Oct4 and Nanog expression, colony and spheroid formation, and migration and invasion abilities in breast cancer cells. In addition, reductions in Oct4, Nanog, and mutp53 expression following rottlerin treatment confirmed the role of pontin in these cells. Therefore, pontin may play a central role in the regulation of CSC properties and in cell proliferation following AST treatment. Taken together, these findings demonstrate that AST can repress CSC stemness genes in breast cancer cells, which implies that AST therapy could be used to improve the efficacy of other anti-cancer therapies against breast cancer cells.

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