scholarly journals Therapeutic Targets and Tumor Microenvironment in Colorectal Cancer

2021 ◽  
Vol 10 (11) ◽  
pp. 2295
Author(s):  
Gaetano Gallo ◽  
Giuseppina Vescio ◽  
Gilda De Paola ◽  
Giuseppe Sammarco
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Suppressor Cells ◽  
Cell Types ◽  
Therapeutic Agents ◽  
New Drugs ◽  
Dynamic Composition ◽  
Pathological Conditions ◽  
Fertile Ground

Colorectal cancer (CRC) is a genetically, anatomically, and transcriptionally heterogeneous disease. The prognosis for a CRC patient depends on the stage of the tumor at diagnosis and widely differs accordingly. The tumor microenvironment (TME) in CRC is an important factor affecting targeted cancer therapy. The TME has a dynamic composition including various cell types, such as cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, as well as extracellular factors that surround cancer cells and have functional and structural roles under physiological and pathological conditions. Moreover, the TME can limit the efficacy of therapeutic agents through high interstitial pressure, fibrosis, and the degradation of the therapeutic agents by enzymatic activity. For this reason, the TME is a fertile ground for the discovery of new drugs. The aim of this narrative review is to present current knowledge and future perspectives regarding the TME composition based on strategies for patients with CRC.

scholarly journals Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1627 ◽  
Author(s):  
Anita Thyagarajan ◽  
Mamdouh Salman A. Alshehri ◽  
Kelly L.R. Miller ◽  
Catherine M. Sherwin ◽  
Jeffrey B. Travers ◽  
...  
Keyword(s):  
Survival Rates ◽  
Suppressor Cells ◽  
Cell Types ◽  
Therapeutic Agents ◽  
Ductal Adenocarcinoma ◽  
Cancer Therapies ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Resistance ◽  
Cellular Mechanisms ◽  
Immunosuppressive Cell

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

scholarly journals The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment

2020 ◽  
Author(s):  
Mohammad H. Rashid ◽  
Thaiz F. Borin ◽  
Roxan Ara ◽  
Raziye Piranlioglu ◽  
Bhagelu R. Achyut ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Cell Types ◽  
Biological Macromolecules

AbstractMyeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.

Myeloid-Derived Suppressor Cells in the Tumor Microenvironment: Current Knowledge and Future Perspectives

2017 ◽  
Vol 66 (2) ◽  
pp. 113-123 ◽  
Author(s):  
Maria Ibáñez-Vea ◽  
Miren Zuazo ◽  
Maria Gato ◽  
Hugo Arasanz ◽  
Gonzalo Fernández-Hinojal ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Future Perspectives

scholarly journals Chemokines—What Is Their Role in Colorectal Cancer?

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482090338 ◽  
Author(s):  
Sara Pączek ◽  
Marta Łukaszewicz-Zając ◽  
Barbara Mroczko
Keyword(s):  
Colorectal Cancer ◽  
Current Knowledge ◽  
Early Stage ◽  
Distant Metastases ◽  
Cell Types ◽  
Diagnosis And Prognosis ◽  
Novel Biomarkers ◽  
Specific Receptors ◽  
Common Malignancy

Colorectal cancer (CRC) is one of the leading causes of cancer-related death. It is the second most frequently diagnosed malignancy in Europe and third worldwide. Colorectal malignancies diagnosed at an early stage offer a promising survival rate. However, advanced tumors often present distant metastases even after the complete resection of a primary tumor. Therefore, novel biomarkers of CRC are sorely needed in the diagnosis and prognosis of this common malignancy. A family of chemokines are composed of small, secreted proteins. They are best known for their ability to stimulate the migration of several cell types. Some investigations have indicated that chemokines are involved in cancer development, including CRC. This article presents current knowledge regarding chemokines and their specific receptors in CRC progression. Moreover, the prime aim of this review is to summarize the potential role of these proteins as biomarkers in the diagnosis and prognosis of CRC.

scholarly journals Immune and Inflammatory Cells of the Tumor Microenvironment Represent Novel Therapeutic Targets in Classical Hodgkin Lymphoma

2019 ◽  
Vol 20 (21) ◽  
pp. 5503 ◽  
Author(s):  
Eleonora Calabretta ◽  
Francesco d’Amore ◽  
Carmelo Carlo-Stella
Keyword(s):  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
Suppressor Cells ◽  
Inflammatory Cells ◽  
Brentuximab Vedotin ◽  
New Drugs ◽  
Classical Hodgkin Lymphoma ◽  
Relevant Role

Classical Hodgkin Lymphoma (cHL) is a B-cell malignancy that, typically, responds well to standard therapies. However, patients who relapse after standard regimens or are refractory to induction therapy have a dismal outcome. The implementation of novel therapies such as the anti-CD30 monoclonal antibody Brentuximab Vedotin and immune checkpoint inhibitors has provided curative options for many of these patients. Nonetheless, responses are rarely durable, emphasizing the need for new agents. cHL is characterized by a unique microenvironment in which cellular and humoral components interact to promote tumor survival and dissemination. Knowledge of the complex composition of cHL microenvironment is constantly evolving; in particular, there is growing interest in certain cell subsets such as tumor-associated macrophages, myeloid-derived suppressor cells and neutrophils, all of which have a relevant role in the pathogenesis of the disease. The unique biology of the cHL microenvironment has provided opportunities to develop new drugs, many of which are currently being tested in preclinical and clinical settings. In this review, we will summarize novel insights in the crosstalk between tumor cells and non-malignant inflammatory cells. In addition, we will discuss the relevance of tumor-microenvironment interactions as potential therapeutic targets.

Network analysis to reveal BTK as a link between myeloid and T cells in TLR signaling in colorectal cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 30-30
Author(s):  
Justin Hummel ◽  
Yuanyuan Shen ◽  
Iiulia Innokenteva ◽  
Christos Papageorgiou ◽  
Chi-Ren Shyu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Network Analysis ◽  
Tumor Microenvironment ◽  
Myeloid Cells ◽  
Cell Types ◽  
The Cancer Genome Atlas ◽  
P Value ◽  
Tlr Signaling ◽  
Critical Link

30 Background: Colorectal cancer (CRC) is the second-leading cause of cancer mortality in the US today. Recent advances in immunotherapy have only been shown to benefit a limited subgroup of patients with CRC. In other malignancies, activation of Toll-like receptors (TLRs) has been shown to overcome resistance to immunotherapy, such as immune checkpoint inhibition (ICI). In this study, using publicly available data and informatics-based analysis, we identified BTK as a critical link between TLR signaling and T cells in the CRC tumor microenvironment. Methods: Using RNA-seq data from The Cancer Genome Atlas (TCGA) and the Microenvironment Cell Populations (MCP)-Counter, abundance scores were generated for the tumor microenvironment of each patient. A curated TLR gene panel was generated using Reactome and GO. Pearson analysis was used to evaluate each pairwise combination of genes and cell-types. Significance was determined by the correlation coefficient, r ≥ | 0.7 | with a p-value < 0.05. Network analysis was performed using the Girvan–Newman algorithm to establish critical connections across these features. Results: After establishing a 453 gene TLR panel and creating MCP-Counter scores, correlation analysis demonstrated strong correlations between 54 different genes and 7 cell-types. As expected the most genes were associated with monocytic lineage cells' (30) and 'myeloid dendritic cells' (7). Only 5 genes were significantly associated with 'T cells'. Genes and cell-types that were highly correlated were then further analyzed for network association. From this analysis, BTK was identified as a critical edge acting as the primary link between ‘myeloid cells’ and ‘T cells’. Conclusions: Developing novel strategies for the treatment of CRC is critical and immunotherapy represents an area ripe for advancement. Informatics based analysis combined with publicly available data provides us with an opportunity to shape pre-clinical and translational studies. Using this approach, we have identified BTK as a critical link between myeloid cells and T cells in the tumor microenvironment in CRC. Further studies in our laboratory will focus confirming these findings for translation into patients.

scholarly journals The Role of Tumor Microenvironment Cells in Colorectal Cancer (CRC) Cachexia

2021 ◽  
Vol 22 (4) ◽  
pp. 1565
Author(s):  
Aldona Kasprzak
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Systemic Inflammation ◽  
Cancer Cachexia ◽  
Current Knowledge ◽  
Colorectal Cancer Cells ◽  
Factor Α ◽  
Cellular Components

Cancer cachexia (CC) is a multifactorial syndrome in patients with advanced cancer characterized by weight loss via skeletal-muscle and adipose-tissue atrophy, catabolic activity, and systemic inflammation. CC is correlated with functional impairment, reduced therapeutic responsiveness, and poor prognosis, and is a major cause of death in cancer patients. In colorectal cancer (CRC), cachexia affects around 50–61% of patients, but remains overlooked, understudied, and uncured. The mechanisms driving CC are not fully understood but are related, at least in part, to the local and systemic immune response to the tumor. Accumulating evidence demonstrates a significant role of tumor microenvironment (TME) cells (e.g., macrophages, neutrophils, and fibroblasts) in both cancer progression and tumor-induced cachexia, through the production of multiple procachectic factors. The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called “cachexokines”. The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis. This review summarizes the current knowledge on the role of TME cellular components in CRC-associated cachexia, as well as discusses the potential role of selected mediators secreted by colorectal cancer cells in cooperation with tumor-associated immune and non-immune cells of tumor microenvironment in inducing or potentiating cancer cachexia. This knowledge serves to aid the understanding of the mechanisms of this process, as well as prevent its consequences.

scholarly journals Delineation of colorectal cancer ligand-receptor interactions and their roles in the tumor microenvironment and prognosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hexin Lin ◽  
Lu Xia ◽  
Jiabian Lian ◽  
Yinan Chen ◽  
Yiyi Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Types ◽  
Clinical Value ◽  
Tumor Subtypes ◽  
Receptor Interactions ◽  
New Ideas ◽  
Potential Ligand ◽  
Infiltrating Lymphocytes

Abstract Background Immunotherapies targeting ligand-receptor interactions (LRIs) are advancing rapidly in the treatment of colorectal cancer (CRC), and LRIs also affect many aspects of CRC development. However, the pattern of LRIs in CRC and their effect on tumor microenvironment and clinical value are still unclear. Methods We delineated the pattern of LRIs in 55,539 single-cell RNA sequencing (scRNA-seq) samples from 29 patients with CRC and three bulk RNA-seq datasets containing data from 1411 CRC patients. Then the influence of tumor microenvironment, immunotherapy and prognosis of CRC patients were comprehensively investigated. Results We calculated the strength of 1893 ligand-receptor pairs between 25 cell types to reconstruct the spatial structure of CRC. We identified tumor subtypes based on LRIs, revealed the relationship between the subtypes and immunotherapy efficacy and explored the ligand-receptor pairs and specific targets affecting the abundance of tumor-infiltrating lymphocytes. Finally, a prognostic model based on ligand-receptor pairs was constructed and validated. Conclusion Overall, through the comprehensive and in-depth investigation of the existing ligand-receptor pairs, this study provides new ideas for CRC subtype classification, a new risk screening tool for CRC patients, and potential ligand-receptor pair targets and pathways for CRC therapy.

The Disposal of Reactive Carbonyl Species through Carnosine Conjugation: What We Know Now

2020 ◽  
Vol 27 (11) ◽  
pp. 1726-1743 ◽  
Author(s):  
Ettore Gilardoni ◽  
Giovanna Baron ◽  
Alessandra Altomare ◽  
Marina Carini ◽  
Giancarlo Aldini ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Current Knowledge ◽  
Therapeutic Agents ◽  
New Drugs ◽  
Reactive Carbonyl Species ◽  
Carbonyl Species ◽  
Reactive Carbonyl

: Reactive Carbonyl Species are electrophiles generated by the oxidative cleavage of lipids and sugars. Such compounds have been described as important molecules for cellular signaling, whilst their accumulation has been found to be cytotoxic as they may trigger aberrant modifications of proteins (a process often referred to as carbonylation). : A correlation between carbonylation of proteins and human disease progression has been shown in ageing, diabetes, obesity, chronic renal failure, neurodegeneration and cardiovascular disease. However, the fate of reactive carbonyl species is still far from being understood, especially concerning the mechanisms responsible for their disposal as well as the importance of this in disease progression. : In this context, some data have been published on phase I and phase II deactivation of reactive carbonyl species. In the case of phase II mechanisms, the route involving glutathione conjugation and subsequent disposal of the adducts has been extensively studied both in vitro and in vivo for some of the more representative compounds, e.g. 4-hydroxynonenal. : There is also emerging evidence of an involvement of carnosine as an endogenous alternative to glutathione for phase II conjugation. However, the fate of carnosine conjugates is still poorly investigated and, unlike glutathione, there is little evidence of the formation of carnosine adducts in vivo. The acquisition of such data could be of importance for the development of new drugs, since carnosine and its derivatives have been proposed as potential therapeutic agents for the mitigation of carbonylation associated with disease progression. : Herein, we wish to review our current knowledge of the binding of reactive carbonyl species with carnosine together with the disposal of carnosine conjugates, emphasizing those aspects still requiring investigation such as conjugation reversibility and enzyme assisted catalysis of the reactions.

scholarly journals Myeloid Cells in Circulation and Tumor Microenvironment of Colorectal Cancer Patients with Early and Advanced Disease Stages

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Salman M. Toor ◽  
Sarah Khalaf ◽  
Khaled Murshed ◽  
Mohamed Abu Nada ◽  
Eyad Elkord
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Whole Blood ◽  
Advanced Disease ◽  
Current Knowledge ◽  
Prognostic Significance ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Disease Stages

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells that have been implicated in the development of an immunosuppressive environment, which promotes tumorigenesis and tumor progression. Numerous studies have reported expansion of MDSCs in circulation and the tumor microenvironment (TME) of cancer patients. However, due to the heterogenic nature of MDSCs and the different approaches for their identification, their detailed characterization and impact on disease progression in cancer patients are warranted. In this study, we investigated the levels of different myeloid cell subsets and antigen-presenting cells (APCs) using flow cytometry in unfractionated whole blood (WB), peripheral blood mononuclear cells (PBMCs), tumor tissue (TT), and adjacent normal tissue (NT) of colorectal cancer (CRC) patients. We found high levels of granulocytic myeloid cells (GMCs) in whole blood, but their levels were significantly lower in PBMCs. Importantly, we found significantly higher levels of GMCs in the TME compared to NT. In addition, monocytic myeloid cells (MMCs) showed significantly higher levels in PBMCs of CRC patients, compared to healthy donors (HDs). Notably, patients with advanced disease stages showed significantly higher levels of GMCs compared to early stages in whole blood, but PBMCs and tumor-infiltrating myeloid cells did not show any significant differences. Lastly, we found that levels of GMCs decreased, while IMCs increased in the TME with tumor budding. Our results highlight the importance of investigating the levels of different myeloid cell subsets in PBMCs versus whole blood of cancer patients and improve current knowledge on the potential prognostic significance of myeloid cells in CRC patients.

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