scholarly journals Immune Escape Mechanisms in Colorectal Cancer Pathogenesis and Liver Metastasis

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Massimo Pancione ◽  
Guido Giordano ◽  
Andrea Remo ◽  
Antonio Febbraro ◽  
Lina Sabatino ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Immune Escape ◽  
De Novo ◽  
Tumour Progression ◽  
Therapy Resistance ◽  
Phenotypic Traits ◽  
Metastatic Progression ◽  
Malignant Cells ◽  
Cancer Pathogenesis

Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced orde novosynthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance.

scholarly journals 736 Treatment with decitabine (DAC) induces the expression of stemness markers, PD-L1 and NY-ESO-1 in colorectal cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A767-A767
Author(s):  
Nassiba Taib ◽  
Maysaloun Merhi ◽  
Varghese Inchakalody ◽  
Sarra Mestiri ◽  
Afsheen Raza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
New York ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Tumor Antigen ◽  
Immune Escape ◽  
Combined Treatment ◽  
Cpg Islands ◽  
Dna Demethylation

BackgroundColorectal cancer (CRC) is a leading cause of cancer related deaths. Epigenetic silencing of numerous tumor suppressor genes by promoter region hypermethylation has been found in a variety of cancers including CRC. The chemotherapeutic drug decitabine (DAC) is a strong inducer of DNA demethylation. Primary cancer cells are known to express stemness markers as an escape pathway of treatment. Moreover, immunoregulatory genes can be inactivated in these cells by methylation of promoter CpG islands. Both mechanisms are known to play crucial roles in tumor progression. In this study, we investigated the effect of DAC on the expression of stemness markers, Programmed cell death ligand (PD-L1) and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) in a metastatic (1872 Col) and a primary (1076 Col) colorectal cancer cell lines isolated from patients' tumor tissues.MethodsThe 1076 Col and 1872 Col cell lines were treated with 5 μM of DAC for 48 hours. Differential expression of a panel of stemness and immunoregulatory markers before and after treatment was analyzed by Flow cytometry (FACS), Western Blotting (WB) and quantitative real time PCR (qRT-PCR).ResultsThe following stemness markers: CD44, Nanog, KLF-4, CD133 and MSI1 were up-regulated in both 1076 Col and 1872 Col cell lines after treatment. However, significant up-regulation of the immunoinhibitory PD-L1 marker was recorded after treatment only in the metastatic 1872 Col. Interestingly, the NY-ESO-1 tumor antigen was significantly upregulated in both 1076 Col and 1872 Col cell lines after treatment.ConclusionsTreatment of colon cancer cells with DAC induces chemotherapeutic resistance as evidenced by the induction/upregulation of the stemness markers; and immune escape mechanism through the induction/upregulation of PD-L1. However, such treatment resulted in the induction/expression of the most immunogenic NY-ESO-1 tumor antigen. Our data suggest the importance use of a combined treatment strategy utilizing chemotherapy (DAC) with anti-PD-L-1/PD-1treatment in colon cancer patients.Ethics ApprovalThe study obtained ethical approval from Hamad Medical Corporation, Medical Research Center Ethic Board: Grant ID : IRGC-04-SI-17-142.

scholarly journals Blood Vessels and Peripheral Nerves as Key Players in Cancer Progression and Therapy Resistance

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4471
Author(s):  
Niccolò Roda ◽  
Giada Blandano ◽  
Pier Giuseppe Pelicci
Keyword(s):  
Cancer Cells ◽  
Blood Vessels ◽  
Cancer Progression ◽  
Peripheral Nerves ◽  
Tumor Development ◽  
Therapy Resistance ◽  
Tumor Mass ◽  
Cancer Pathogenesis ◽  
Initial Results ◽  
Metastatic Spreading

Cancer cells continuously interact with the tumor microenvironment (TME), a heterogeneous milieu that surrounds the tumor mass and impinges on its phenotype. Among the components of the TME, blood vessels and peripheral nerves have been extensively studied in recent years for their prominent role in tumor development from tumor initiation. Cancer cells were shown to actively promote their own vascularization and innervation through the processes of angiogenesis and axonogenesis. Indeed, sprouting vessels and axons deliver several factors needed by cancer cells to survive and proliferate, including nutrients, oxygen, and growth signals, to the expanding tumor mass. Nerves and vessels are also fundamental for the process of metastatic spreading, as they provide both the pro-metastatic signals to the tumor and the scaffold through which cancer cells can reach distant organs. Not surprisingly, continuously growing attention is devoted to the development of therapies specifically targeting these structures, with promising initial results. In this review, we summarize the latest evidence that supports the importance of blood vessels and peripheral nerves in cancer pathogenesis, therapy resistance, and innovative treatments.

scholarly journals Correction: Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway

2020 ◽  
Vol 27 (7) ◽  
pp. 2293-2293
Author(s):  
Chao Liu ◽  
Zhaoying Yao ◽  
Jianing Wang ◽  
Wen Zhang ◽  
Yan Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Immune Escape ◽  
Colorectal Cancer Cells

scholarly journals Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis

2021 ◽  
Author(s):  
Nicole Kiweler ◽  
Catherine Delbrouck ◽  
Laura Neises ◽  
Vitaly Pozdeev ◽  
Leticia Soriano-Baguet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Carbon Cycle ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
De Novo ◽  
Prolonged Treatment ◽  
Tumor Escape ◽  
Metastatic Progression ◽  
Nucleotide Synthesis

Abstract Progression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs mainly target the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Thus, we aimed to identify metabolic determinants that enable cell plasticity and foster treatment resistance and tumor escape. Using a panel of anti-cancer drugs, we uncovered that antifolates, despite inducing strong growth arrest, did not impact the cancer cell’s motility potential, indicating that nucleotide synthesis is dispensable for cell motility. Prolonged treatment even selected for more motile cancer subpopulations. We found that cytosolic inhibition of DHFR by MTX only abrogates cytosolic folate cycle, while mitochondrial one-carbon cycle remains highly active. Despite a decreased cellular demand for biomass production, de novo serine synthesis and formate overflow are increased, suggesting that mitochondria provide a protective environment that allows serine catabolism to support cellular motility during nucleotide synthesis inhibition. Enhanced motility of growth-arrested cells was reduced by inhibition of PHGDH-dependent de novo serine synthesis and genetic silencing of mitochondrial one-carbon cycle. In vivo targeting of mitochondrial one-carbon cycle and formate overflow strongly and significantly reduced lung metastasis formation in an orthotopic breast cancer model. In summary, we identified mitochondrial serine catabolism as a targetable, growth-independent metabolic vulnerability to limit metastatic progression.

scholarly journals The Role of Tumor-Stroma Interactions in Drug Resistance Within Tumor Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanghong Ni ◽  
Xiaoting Zhou ◽  
Jia Yang ◽  
Houhui Shi ◽  
Hongyi Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Escape ◽  
Suppressor Cells ◽  
Tumor Stroma ◽  
Malignant Cells ◽  
Acquired Drug Resistance ◽  
Long Time

Cancer cells resistance to various therapies remains to be a key challenge nowadays. For a long time, scientists focused on tumor cells themselves for the mechanisms of acquired drug resistance. However, recent evidence showed that tumor microenvironment (TME) is essential for regulating immune escape, drug resistance, progression and metastasis of malignant cells. Reciprocal interactions between cancer cells and non-malignant cells within this milieu often reshape the TME and promote drug resistance. Therefore, advanced knowledge about these sophisticated interactions is significant for the design of effective therapeutic approaches. In this review, we highlight cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory lymphocytes (Tregs), mesenchymal stem cells (MSCs), cancer-associated adipocytes (CAAs), and tumor endothelial cells (TECs) existing in TME, as well as their multiple cross-talk with tumor cells, which eventually endows tumor cells with therapeutic resistance.

State-of-the-Art: Exosomes in Colorectal Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Yan Dang ◽  
Shutian Zhang ◽  
Yongjun Wang ◽  
Guiping Zhao ◽  
Chuyan Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mortality Rate ◽  
Cancer Cells ◽  
Stromal Cells ◽  
State Of The Art ◽  
Therapy Resistance ◽  
Clinical Applications ◽  
Bioactive Molecules ◽  
High Prevalence ◽  
Cancerous Cells

: Colorectal cancer (CRC) has a high prevalence and mortality rate, globally. To date, the progression mechanisms of CRC are still elusive. Exosomes (~100 nm in diameter) correspond to a subset of extracellular vesicles formed by an array of cancerous cells and stromal cells. These particular nanovesicles carry and transmit bioactive molecules, like proteins, lipids, and genetic materials, which mediate the crosstalk between cancer cells and the microenvironment. Accumulating evidence has shown the decisive functions of exosomes in the development, metastasis, and therapy resistance of CRC. Furthermore, some recent studies have also revealed the abilities of exosomes to function as either biomarkers or therapeutic targets for CRC. This review focuses on the specific mechanisms of exosomes in regulating CRC progression, and summarizes the potential clinical applications of exosomes in the diagnosis and therapy of CRC.

scholarly journals Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway

2019 ◽  
Vol 27 (6) ◽  
pp. 1765-1781 ◽  
Author(s):  
Chao Liu ◽  
Zhaoying Yao ◽  
Jianing Wang ◽  
Wen Zhang ◽  
Yan Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Immune Escape ◽  
Colorectal Cancer Cells

scholarly journals Role of extracellular vesicles in tumour microenvironment

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Shi-Cong Tao ◽  
Shang-Chun Guo
Keyword(s):  
Extracellular Vesicles ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Tumour Progression ◽  
Malignant Tumour ◽  
Tumour Microenvironment ◽  
Future Research ◽  
Malignant Cells ◽  
Malignant Tumours ◽  
Mesenchymal Transition

Abstract In recent years, it has been demonstrated that extracellular vesicles (EVs) can be released by almost all cell types, and detected in most body fluids. In the tumour microenvironment (TME), EVs serve as a transport medium for lipids, proteins, and nucleic acids. EVs participate in various steps involved in the development and progression of malignant tumours by initiating or suppressing various signalling pathways in recipient cells. Although tumour-derived EVs (T-EVs) are known for orchestrating tumour progression via systemic pathways, EVs from non-malignant cells (nmEVs) also contribute substantially to malignant tumour development. Tumour cells and non-malignant cells typically communicate with each other, both determining the progress of the disease. In this review, we summarise the features of both T-EVs and nmEVs, tumour progression, metastasis, and EV-mediated chemoresistance in the TME. The physiological and pathological effects involved include but are not limited to angiogenesis, epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) remodelling, and immune escape. We discuss potential future directions of the clinical application of EVs, including diagnosis (as non-invasive biomarkers via liquid biopsy) and therapeutic treatment. This may include disrupting EV biogenesis and function, thus utilising the features of EVs to repurpose them as a therapeutic tool in immunotherapy and drug delivery systems. We also discuss the overall findings of current studies, identify some outstanding issues requiring resolution, and propose some potential directions for future research.

SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

Gut ◽  
2017 ◽  
Vol 68 (1) ◽  
pp. 118-129 ◽  
Author(s):  
Ledong Wan ◽  
Wenying Yu ◽  
Enhui Shen ◽  
Wenjie Sun ◽  
Yuan Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Alternative Splicing ◽  
De Novo ◽  
Tumour Progression ◽  
The Cancer Genome Atlas ◽  
Chronic Obstructive ◽  
Binding Motif ◽  
Sequencing Data

ObjectiveTo investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6.DesignWe performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo. SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay. ZO-1 exon23 AS was investigated to mediate the function of SRSF6 in vitro and in vivo. Based on the analysis of domain-specific role, SRSF6-targeted inhibitor was discovered de novoby virtual screening in 4855 FDA-approved drugs and its antitumour effects were evaluated in vitroand in vivo.ResultsSRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo. We identified SRSF6-regulated AS targets and discovered the SRSF6 binding motif. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a β2-adrenergic receptor agonist approved for chronic obstructive pulmonary disease treatment, is identified as the inhibitor of SRSF6 to suppress CRC tumourigenicity.ConclusionsSRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6.Accession numbersThe accession numbers for sequencing data are SRP111763 and SRP111797.

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