scholarly journals Integrins Within the Tumor Microenvironment: Biological Functions, Importance for Molecular Targeting, and Cancer Therapeutics Innovation

2021 ◽  
Author(s):  
Kevin Dzobo
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Therapeutics ◽  
Molecular Targeting ◽  
Biological Functions

scholarly journals MicroRNAs as Emerging Regulators of Signaling in the Tumor Microenvironment

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 911 ◽  
Author(s):  
Shahzad Nawaz Syed ◽  
Bernhard Brüne
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathways ◽  
Target Identification ◽  
Cancer Therapeutics ◽  
Protein Translation ◽  
Transcriptional Gene Silencing ◽  
Post Transcriptional Gene Silencing ◽  
Cancer Initiation ◽  
Regulate Protein

A myriad of signaling molecules in a heuristic network of the tumor microenvironment (TME) pose a challenge and an opportunity for novel therapeutic target identification in human cancers. MicroRNAs (miRs), due to their ability to affect signaling pathways at various levels, take a prominent space in the quest of novel cancer therapeutics. The role of miRs in cancer initiation, progression, as well as in chemoresistance, is being increasingly investigated. The canonical function of miRs is to target mRNAs for post-transcriptional gene silencing, which has a great implication in first-order regulation of signaling pathways. However, several reports suggest that miRs also perform non-canonical functions, partly due to their characteristic non-coding small RNA nature. Examples emerge when they act as ligands for toll-like receptors or perform second-order functions, e.g., to regulate protein translation and interactions. This review is a compendium of recent advancements in understanding the role of miRs in cancer signaling and focuses on the role of miRs as novel regulators of the signaling pathway in the TME.

scholarly journals Comprehensive analysis of tumor microenvironment landscape and potential therapeutic agents based on tumor-infiltrating immune cells in colorectal cancer

2021 ◽  
Author(s):  
Wenhui Zhong ◽  
Feng Zhang ◽  
Xin Lu ◽  
Kaijun Huang ◽  
Junming Bi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Cancer Therapeutics ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction ◽  
Chemotherapy Drugs ◽  
Drug Compounds

Abstract Background: Tumor-infiltrating immune cells (TIIC) are the major components of the tumor microenvironment (TME) and play vital roles in the tumorigenesis and progression of colorectal cancer (CRC). Increasing evidence has elucidated their significances in predicting prognosis and therapeutic efficacy. Nonetheless, the immune infiltrative landscape of CRC remains largely unknown. Methods: All the RNA-seq transcriptome data and full clinical annotation of 1213 colorectal cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene-Expression Omnibus (GEO) database. The “CIBERSORT” and “estimate” R package were applied to calculate 22 infiltrated immune cell fractions and stromal and immune score. Three TIIC patterns were determined by Unsupervised clustering methods. Through using principal-component analysis, TIIC scores were established. Data for potential agents comes from the Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) and Cancer Therapeutics Response Portal database (CTRP). Results：In this study, we identified three distinct TIIC patterns characterized by distinct immunological features in 1213 CRC samples from multiple platforms. Base on the TIIC-related gene signatures from three clusters, we constructed a scoring system to quantify the immune infiltration level of individual samples in the CRC cohort and the clinical benefits of different groups. The high TIIC score group was marked by increased immune activation status and favorable prognosis. Conversely, low TIIC score group was featured with immune-desert phenotype and poor prognosis, along with the activation of transforming growth factor-β (TGF-β), WNT, ECM receptor interaction, and VEGF signaling pathways. Meanwhile, the high TIIC score group was also correlated with enhanced efficacy of immunotherapy. Additional, four chemotherapy drugs, seven CTRP-derived drug compounds and six PRISM-derived drug compounds were identified as potential drug for CRC among high and low TIIC subgroups.Conclusions: Collectively, as an effective prognostic biomarker and predictive indicator, the TIIC score plays an important role in the evaluation of CRC prognosis and the response of immunotherapy. Investigation of the TIIC patterns might provide us a promising target for improving immunotherapeutic efficacy in CRC.

Instructed-Assembly as Context-Dependent Nanoscale Signals for Death and Morphogenesis of Cells

2019 ◽  
Author(s):  
Huaimin Wang ◽  
Zhaoqianqi Feng ◽  
Bing Xu
Keyword(s):  
Cell Death ◽  
Enzyme Activity ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Drug Screening ◽  
Cell Behavior ◽  
Biological Functions ◽  
Cell Spheroids ◽  
Cellular Environment ◽  
Context Dependent

Context-dependent signaling, as a ubiquitous phenomenon in nature, is a dynamic molecular process at nano- and microscales, but how to mimic its essence using non-covalent synthesis in cellular environment has yet to be developed. Here we show a dynamic continuum of non-covalent filaments formed by instructed-assembly (iA) of a supramolecular phosphoglycopeptide (sPGP) as context-dependent signals for controlling death and morphogenesis of cells. Specifically, while enzymes (i.e., ectophosphatases) on cancer cells catalyze the formation of the filaments of the sPGP to result in cell death, damping the enzyme activity induces 3D cell spheroids. Similarly, relying on the ratio of stromal and cancer cells in a co-culture to modulate the expression of the ectophosphatase, the iA process enables cell spheroids. The spheroids act as a mimic of tumor microenvironment for drug screening. As the first demonstration of iA as multifunctional processes according to local enzyme activity for controlling cell behavior, this work illustrates context-dependent biological functions of non-covalent synthesis in cellular environment.

scholarly journals Anti-EGFR Fibronectin Bispecific Chemically Self-Assembling Nanorings (CSANs) Induce Potent T cell Mediated Anti-Tumor Response and Downregulation of EGFR Signaling and PD-1/PD-L1 Expression

2020 ◽  
Author(s):  
Ozgun Kilic ◽  
Marcos R. Matos de Souza ◽  
Abdulaziz A. Almotlak ◽  
Jill M. Siegfried ◽  
Carston R. Wagner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Antigens ◽  
Cancer Therapeutics ◽  
High Avidity ◽  
Egfr Signaling ◽  
Single Chain

ABSTRACTNumerous approaches have targeted the Epidermal Growth Factor Receptor (EGFR) for the development of anti-cancer therapeutics, since it is over-expressed on a variety of cancers. Recently, αEGFR chimeric antigen receptor (CAR)-T cells have shown potential promise for the immunological control of tumors. Our laboratory has recently demonstrated that bispecific chemically self-assembled nanorings (CSANs) can modify T cell surfaces and function as prosthetic antigen receptors (PARs). This technology allows selective targeting of tumor antigens due to high avidity of the multimeric rings, while incorporating a mechanism to dissociate the rings to prevent further T cell stimulation. Previously, PARs with single-chain variable fragments (scFvs) have been successful in vitro and in vivo, activating T cells selectively at the tumor site. Alternatively, here we report fibronectin (FN3)-based PARs with improved properties such as increased protein yield, rapid protein production, increased protein stability and predicted low immunogenicity due to the human origin of fibronectins. We examined the cytotoxicity of EGFR-targeting PARs in vitro in which the affinities of the αEGFR fibronectins, the αEGFR/ αCD3 valency of the CSANs and the antigen expression levels were varied. Based on these selective in vitro cytotoxicity results, we conducted an in vivo study of FN3-PARs using an orthotopic breast cancer model. The FN3-PARs demonstrated potent tumor growth suppression with no adverse effects. Furthermore, these results demonstrated that FN3-PARs modulated the tumor microenvironment by downregulating EGFR signaling resulting in decreased PD-L1 expression. In addition, the expression of PD-1 was also found to be reduced. Collectively, these results demonstrate that FN3-PARs have the potential to direct selective T cell targeted tumor killing and that αEGFR FN3-PARs may enhance anti-tumor T cell efficacy by modulating the tumor microenvironment.

scholarly journals LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency

2020 ◽  
Author(s):  
Marie N. O’Connor ◽  
David M. Kallenberg ◽  
Rene Jackstadt ◽  
Angharad H. Watson ◽  
Markella Alatsatianos ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Effective Means ◽  
Cancer Therapeutics ◽  
Adoptive T Cell Therapy ◽  
Significant Shift ◽  
T Cell Therapy ◽  
Blocking Antibody ◽  
Pericyte Coverage

ABSTRACTVascular dysfunction contributes to the pro-oncogenic tumor microenvironment and impedes the delivery of therapeutics. Normalizing of the tumor vasculature has therefore become a potential therapeutic objective. We previously reported that the secreted glycoprotein, leucine-rich α-2-glycoprotein 1 (LRG1), contributes to the formation of pathogenic neovascularization. Here we show that in mouse models of cancer, Lrg1 is induced in tumor endothelial cells. We demonstrate that the expression of LRG1 impacts on tumor progression as Lrg1 deletion or treatment with a LRG1 function-blocking antibody inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function resulting in significantly enhanced efficacy of cisplatin chemotherapy, adoptive T-cell therapy and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent (cold) to immune active (hot). LRG1 therefore drives vascular abnormalization and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics.

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