scholarly journals The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity

2020 ◽  
Vol 21 (18) ◽  
pp. 6805
Author(s):  
Kyung Chan Park ◽  
Mahendiran Dharmasivam ◽  
Des R. Richardson
Keyword(s):  
Cancer Progression ◽  
Cell Invasion ◽  
Metal Ion ◽  
Membrane Surface ◽  
Specific Antigen ◽  
Cancer Therapeutics ◽  
Matrix Metalloproteases ◽  
Matrix Remodeling ◽  
Extracellular Proteases

The role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include the metal-binding agents di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which increase c-MET degradation by multiple mechanisms. Both the direct and indirect inhibition of protease expression and activity can be achieved through metal ion depletion. Considering direct mechanisms, chelators can bind zinc(II) that plays a catalytic role in enzyme activity. In terms of indirect mechanisms, Dp44mT and DpC potently suppress the expression of the kallikrein-related peptidase—a prostate-specific antigen—in prostate cancer cells. The mechanism of this activity involves promotion of the degradation of the androgen receptor. Additional suppressive mechanisms of Dp44mT and DpC on matrix metalloproteases (MMPs) relate to their ability to up-regulate the metastasis suppressors N-myc downstream regulated gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion.

scholarly journals Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

2019 ◽  
Vol 40 (5) ◽  
pp. 633-642 ◽  
Author(s):  
Divya Bhagirath ◽  
Thao Ly Yang ◽  
Z Laura Tabatabai ◽  
Varahram Shahryari ◽  
Shahana Majid ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Progression ◽  
Specific Antigen ◽  
Tumor Grade ◽  
Clinical Samples ◽  
Mesenchymal Transition ◽  
Microrna Genes

Abstract The prostate cancer (PCa) genome is characterized by deletions of chromosome 8p21–22 region that increase significantly with tumor grade and are associated with poor prognosis. We proposed and validated a novel, paradigm-shifting hypothesis that this region is associated with a set of microRNA genes—miR-3622, miR-3622b, miR-383—that are lost in PCa and play important mechanistic roles in PCa progression and metastasis. Extending our hypothesis, in this study, we evaluated the role of a microRNA gene located in chromosome 8p—miR-4288—by employing clinical samples and cell lines. Our data suggests that (i) miR-4288 is widely downregulated in primary prostate tumors and cell lines; (ii) miR-4288 expression is lost in metastatic castration-resistant PCa; (ii) miR-4288 downregulation is race-related PCa alteration that is prevalent in Caucasian patients and not in African Americans; (iii) in Caucasians, miR-4288 was found to be associated with increasing tumor grade and high serum prostate-specific antigen, suggesting that miR-4288 downregulation/loss may be associated with tumor progression specifically in Caucasians; (iv) miR-4288 possess significant potential as a molecular biomarker to predict aggressiveness/metastasis; and (v) miR-4288 is anti-proliferative, is anti-invasive and inhibits epithelial-to-mesenchymal transition; and (vi) miR-4288 directly represses expression of metastasis/invasion-associated genes MMP16 and ROCK1. Thus, the present study demonstrates a tumor suppressor role for a novel miRNA located with a frequently lost region in PCa, strengthening our hypothesis that this locus is causally related to PCa disease progression via loss of microRNA genes. Our study suggests that miR-4288 may be a novel biomarker and therapeutic target, particularly in Caucasians.

scholarly journals Role of Toll-Like Receptor (TLR)-Signaling in Cancer Progression and Treatment

2020 ◽  
Author(s):  
Shyam Babu Prasad ◽  
Rahul Kumar
Keyword(s):  
Immune Response ◽  
Pattern Recognition ◽  
Cancer Progression ◽  
Cancer Therapeutics ◽  
Tlr Signaling ◽  
Inflammatory Microenvironment ◽  
Cancer Inflammation ◽  
Basic Features

Toll-like receptors (TLRs) are the most essential pattern recognition receptors in mediating the effects of innate immunity. It plays a pivotal role in inducing immune response against a number of pathogens, various diseases conditions including pathogenesis of cancer. Inflammation is often associated with the development and progression of most of cancer, where TLRs interplay very crucial roles. Moreover, TLRs activation can impact the initiation, progression and treatment of cancer by modulating the inflammatory microenvironment. Rapidly growing number of evidences related to TLRs function and expression in cancer cells, suggests its critical association with chemoresistance and tumourigenesis. The current chapter describes the development of various agonist and antagosist for TLRs and their application in cancer therapeutics. The aim of this book chapter is to highlights basic features of TLRs, and its role in cancer progression. It also addresses, how a defect in the TLRs signaling pathway can contributes towards carcinogenesis and recent development of cancer therapeutics that target TLR signaling pathways.

scholarly journals FOXO3a Promotes Tumor Cell Invasion through the Induction of Matrix Metalloproteinases

2009 ◽  
Vol 29 (18) ◽  
pp. 4906-4917 ◽  
Author(s):  
Peter Storz ◽  
Heike Döppler ◽  
John A. Copland ◽  
Kaylene J. Simpson ◽  
Alex Toker
Keyword(s):  
Cancer Progression ◽  
Cell Invasion ◽  
Tumor Metastasis ◽  
Serum Starvation ◽  
Forkhead Transcription Factor ◽  
Nuclear Retention ◽  
Forkhead Transcription Factors ◽  
Human Solid Tumors ◽  
Metalloproteinase 9

ABSTRACT The role of the Forkhead transcription factor FOXO3a in processes that promote tumor metastasis is poorly defined. Here, we show that depletion of FOXO3a from cancer cells leads to decreased tumor size specifically due to attenuated invasive migration. During tumor progression, an increase in tumor mass is concomitant with serum deprivation prior to tumor angiogenesis. We show that nuclear retention of FOXO3a due to serum starvation results in greatly increased cancer cell invasion. Exploration of the mechanism by which FOXO3a promotes invasive migration revealed that it induces the expression of matrix metalloproteinase 9 (MMP-9) and MMP-13, both of which have been causally linked to the invasion and progression of numerous human solid tumors. Our results link Forkhead transcription factors to a previously unexplored function in cancer progression by promoting extracellular matrix degradation, allowing tumors to invade neighboring tissues and ultimately metastasize to distant organs.

scholarly journals IL-33 – positive or negative role in cancer progression?

2019 ◽  
Vol 73 ◽  
pp. 626-635
Author(s):  
Joanna Jarosz ◽  
Diana Papiernik ◽  
Joanna Wietrzyk
Keyword(s):  
Cancer Progression ◽  
Inflammatory Diseases ◽  
Heart Diseases ◽  
Lymphoid Cells ◽  
Antitumor Action ◽  
Dual Function ◽  
Matrix Remodeling ◽  
Interleukin 33 ◽  
Negative Role

Interleukin-33 (IL-33) is a IL-1 family member of cytokines which binds the ST2 (suppression of tumorigenicity 2) receptor. This cytokine has a dual function. It may act both as a traditional cytokine and as an intracellular nuclear factor. IL-33 plays a role in many diseases such as: allergy, inflammatory diseases, diabetes and heart diseases. The role of IL-33 in the development of cancer has been intensively studied in recent years and researchers observe both its pro- -and anti-cancer effects. IL-33 promotes the development of tumors by affecting expression of cytokines promoting proliferation, angiogenesis, migration, matrix remodeling, the inhibition of apoptosis and recruitment of individual cells of the immune system. Antitumor action of IL-33 is carried out by recruiting and activating CD8+T lymphocytes, natural killer (NK) cells and by promoting second type immune response by the type 2 innate lymphoid cells (ILC2). Despite numerous studies on the role of IL-33 in the development of cancer, we still do not fully understand the mechanisms by which IL-33 impacts the development and malignancy of various types of cancers. This review summarizes the dual role of IL-33 in the development of the most common cancers in the world to better understand its importance in the carcinogenesis.

Role of Organ Specific Cancer Stem Cells in Organ Specific Cancer Progression

2020 ◽  
Vol 6 (2) ◽  
pp. 21
Author(s):  
Muhammad Ali ◽  
Fatima Ali ◽  
Nadia Wajid
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Cancer Therapeutics ◽  
Therapeutic Approaches ◽  
Specific Cancer ◽  
Organ Specific

Since the cancer stem cells (CSC) have been identified in 1997 by Bonnet and Dick, more than 100,000 papers have been published on the CSC. Huge research on cancer stem cells helped the scientists to rethink about the cancer therapeutics as classic way of chemotherapy is ineffective because chemotherapy failed to kill these cells, the only reason of cancer relapse. The cancer theory of stem cells is one of the most trending theory in stem cells and cancer biology focusing on the understanding of biology of cancer cells for an enhanced and improved therapeutic approaches should be applied to cure the cancer. This mini-review is a short overview on the role of organ specific cancer stem cells in the organ specific cancer progression.

Emerging Multi-cancer Regulatory Role of ESRP1: Orchestration of Alternative Splicing to Control EMT

2020 ◽  
Vol 20 (9) ◽  
pp. 654-665
Author(s):  
Yellamandayya Vadlamudi ◽  
Debasish K. Dey ◽  
Sun C. Kang
Keyword(s):  
Cell Proliferation ◽  
Alternative Splicing ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Target Genes ◽  
Rna Binding ◽  
Regulatory Protein ◽  
Cancer Therapeutics ◽  
Scientific Data

RNA binding proteins (RBPs) associate with nascent and mature RNAs to perform biological functions such as alternative splicing and RNA stability. Having unique RNA recognition binding motifs, RBPs form complexes with RNA in a sequence- and structure-based manner. Aberrant expressions of several RBPs have been identified in tumorigenesis and cancer progression. These uncontrolled RBPs affect several mechanisms, including cell proliferation, tumor growth, invasion, metastasis and chemoresistance. Epithelial splicing regulatory protein 1 (ESRP1) is a member of the hnRNP family of proteins that play a crucial role in regulating numerous cellular processes, including alternative splicing and translation of multiple genes during organogenesis. Abnormal expression of ESRP1 alters the cell morphology, and leads to cell proliferation and tumor growth during cancer progression. ESRP1 mediated alternative splicing of target genes, including CD44, FGFR, PTBP1, LYN, ENAH, SPAG1 and ZMYND8, results in cancer progression. In addition, ESRP1 also regulates circularization and biogenesis of circular RNAs such as circUHRF1, circNOL10 and circANKS1B, whose expressions have been identified as key factors in various cancers. This multi-functional protein is also involved in imposing stability of target mRNAs such as cyclin A2, and thereby cell cycle regulation. The scope of this review is to examine recent scientific data, outcomes of the up- and down-regulated proteins, and the role of ESRP1 in various cancers. We conclude by summarizing ESRP1 dysregulation and its consequences on target genes in various human cancers. Collectively, the consequences of ESRP1 mediated splicing in cancer cells suggest the role of ESRP1 in cell proliferation and chemoresistance via apoptosis and autophagy modulation, which could, therefore, be potential targets for cancer therapeutics.

scholarly journals Role of the Exosome in Ovarian Cancer Progression and Its Potential as a Therapeutic Target

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1147 ◽  
Author(s):  
Koji Nakamura ◽  
Kenjiro Sawada ◽  
Masaki Kobayashi ◽  
Mayuko Miyamoto ◽  
Aasa Shimizu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Peritoneal Dissemination ◽  
Cancer Therapeutics ◽  
Cell Types ◽  
Target Cells ◽  
Distinct Form ◽  
Cargo Delivery ◽  
Different Cell Types

Peritoneal dissemination is a distinct form of metastasis in ovarian cancer that precedes hematogenic or lymphatic metastasis. Exosomes are extracellular vesicles of 30–150 nm in diameter secreted by different cell types and internalized by target cells. There is emerging evidence that exosomes facilitate the peritoneal dissemination of ovarian cancer by mediating intercellular communication between cancer cells and the tumor microenvironment through the transfer of nucleic acids, proteins, and lipids. Furthermore, therapeutic applications of exosomes as drug cargo delivery are attracting research interest because exosomes are stabilized in circulation. This review highlights the functions of exosomes in each process of the peritoneal dissemination of ovarian cancer and discusses their potential for cancer therapeutics.

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 The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
M. Isabel Palacios-Arreola ◽  
Karen E. Nava-Castro ◽  
Julieta I. Castro ◽  
Eduardo García-Zepeda ◽  
Julio C. Carrero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Cancer Progression ◽  
Chemokine Receptors ◽  
Cancer Therapeutics ◽  
Receptor System ◽  
Small Proteins ◽  
Cancer Pathology ◽  
Breast Cancer Pathology

Chemokines are small proteins that primarily regulate the traffic of leukocytes under homeostatic conditions and during specific immune responses. The chemokine-chemokine receptor system comprises almost 50 chemokines and approximately 20 chemokine receptors; thus, there is no unique ligand for each receptor and the binding of different chemokines to the same receptor might have disparate effects. Complicating the system further, these effects depend on the cellular milieu. In cancer, although chemokines are associated primarily with the generation of a protumoral microenvironment and organ-directed metastasis, they also mediate other phenomena related to disease progression, such as angiogenesis and even chemoresistance. Therefore, the chemokine system is becoming a target in cancer therapeutics. We review the emerging data and correlations between chemokines/chemokine receptors and breast cancer, their implications in cancer progression, and possible therapeutic strategies that exploit the chemokine system.

scholarly journals STIM and ORAI proteins: crucial roles in hallmarks of cancer

2016 ◽  
Vol 310 (7) ◽  
pp. C509-C519 ◽  
Author(s):  
A. Fiorio Pla ◽  
K. Kondratska ◽  
N. Prevarskaya
Keyword(s):  
Cancer Progression ◽  
Cancer Therapeutics ◽  
Cellular Functions ◽  
Hallmarks Of Cancer ◽  
Cellular Processes ◽  
Store Depletion ◽  
Multistep Process ◽  
Intracellular Ca ◽  
Critical Components

Intracellular Ca2+ signals play a central role in several cellular processes; therefore it is not surprising that altered Ca2+ homeostasis regulatory mechanisms lead to a variety of severe pathologies, including cancer. Stromal interaction molecules (STIM) and ORAI proteins have been identified as critical components of Ca2+ entry in both store-dependent (SOCE mechanism) and independent by intracellular store depletion and have been implicated in several cellular functions. In recent years, both STIMs and ORAIs have emerged as possible molecular targets for cancer therapeutics. In this review we focus on the role of STIM and ORAI proteins in cancer progression. In particular we analyze their role in the different hallmarks of cancer, which represent the organizing principle that describes the complex multistep process of neoplastic diseases.

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