scholarly journals miRNAs derived from cancer-associated fibroblasts in colorectal cancer

Epigenomics ◽  
2019 ◽  
Vol 11 (14) ◽  
pp. 1627-1645 ◽  
Author(s):  
Amir Savardashtaki ◽  
Zahra Shabaninejad ◽  
Ahmad Movahedpour ◽  
Roxana Sahebnasagh ◽  
Hamed Mirzaei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Tumor Development ◽  
Complex Interaction ◽  
Cancer Associated Fibroblasts ◽  
Paracrine Signaling ◽  
Cancer Stroma ◽  
The World ◽  
First Time

Currently, the incidence of colorectal cancer (CRC) is increasing across the world. The cancer stroma exerts an impact on the spread, invasion and chemoresistance of CRC. The tumor microenvironment involves a complex interaction between cancer cells and stromal cells, for example, cancer-associated fibroblasts (CAFs). CAFs can promote neoplastic angiogenesis and tumor development in CRC. Mounting evidence suggests that many miRNAs are overexpressed (miR-21, miR-329, miR-181a, miR-199a, miR-382 and miR-215) in CRC CAFs, and these miRNAs can influence the spread, invasiveness and chemoresistance in neighboring tumor cells via paracrine signaling. Herein, we summarize the pathogenic roles of miRNAs and CAFs in CRC. Moreover, for first time, we highlight the miRNAs derived from CRC-associated CAFs and their roles in CRC pathogenesis.

scholarly journals The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6206
Author(s):  
Raghav Chandra ◽  
John D. Karalis ◽  
Charles Liu ◽  
Gilbert Z. Murimwa ◽  
Josiah Voth Park ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Distant Metastases ◽  
Cancer Associated Fibroblasts ◽  
Clinical Strategies ◽  
Cancer Tumor ◽  
Cellular Components ◽  
Common Malignancy ◽  
Related Mortality

Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME.

scholarly journals CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Alessandra Righetti ◽  
Matteo Giulietti ◽  
Berina Šabanović ◽  
Giulia Occhipinti ◽  
Giovanni Principato ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Tumor Invasion ◽  
Epithelial To Mesenchymal Transition ◽  
Current Knowledge ◽  
Tumor Development ◽  
Physiological Role ◽  
Mesenchymal Transition ◽  
Splicing Isoforms

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

scholarly journals Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A

2013 ◽  
Vol 210 (13) ◽  
pp. 2851-2872 ◽  
Author(s):  
Fiorenza Lotti ◽  
Awad M. Jarrar ◽  
Rish K. Pai ◽  
Masahiro Hitomi ◽  
Justin Lathia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cellular Heterogeneity ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblasts ◽  
Self Renewal ◽  
Cytokines And Chemokines ◽  
Response To Chemotherapy ◽  
Cytotoxic Treatment

Many solid cancers display cellular hierarchies with self-renewing, tumorigenic stemlike cells, or cancer-initiating cells (CICs) at the apex. Whereas CICs often exhibit relative resistance to conventional cancer therapies, they also receive critical maintenance cues from supportive stromal elements that also respond to cytotoxic therapies. To interrogate the interplay between chemotherapy and CICs, we investigated cellular heterogeneity in human colorectal cancers. Colorectal CICs were resistant to conventional chemotherapy in cell-autonomous assays, but CIC chemoresistance was also increased by cancer-associated fibroblasts (CAFs). Comparative analysis of matched colorectal cancer specimens from patients before and after cytotoxic treatment revealed a significant increase in CAFs. Chemotherapy-treated human CAFs promoted CIC self-renewal and in vivo tumor growth associated with increased secretion of specific cytokines and chemokines, including interleukin-17A (IL-17A). Exogenous IL-17A increased CIC self-renewal and invasion, and targeting IL-17A signaling impaired CIC growth. Notably, IL-17A was overexpressed by colorectal CAFs in response to chemotherapy with expression validated directly in patient-derived specimens without culture. These data suggest that chemotherapy induces remodeling of the tumor microenvironment to support the tumor cellular hierarchy through secreted factors. Incorporating simultaneous disruption of CIC mechanisms and interplay with the tumor microenvironment could optimize therapeutic targeting of cancer.

scholarly journals Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

2021 ◽  
Vol 12 ◽  
Author(s):  
Pei-Yu Chen ◽  
Wen-Fei Wei ◽  
Hong-Zhen Wu ◽  
Liang-Sheng Fan ◽  
Wei Wang
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Regulation ◽  
Stromal Cells ◽  
Cancer Associated Fibroblasts ◽  
Immune Microenvironment ◽  
Cancer Associated Fibroblast ◽  
Different Origins ◽  
Fibroblast Heterogeneity

Cancer-associated fibroblasts (CAFs) are important, highly heterogeneous components of the tumor extracellular matrix that have different origins and express a diverse set of biomarkers. Different subtypes of CAFs participate in the immune regulation of the tumor microenvironment (TME). In addition to their role in supporting stromal cells, CAFs have multiple immunosuppressive functions, via membrane and secretory patterns, against anti-tumor immunity. The inhibition of CAFs function and anti-TME therapy targeting CAFs provides new adjuvant means for immunotherapy. In this review, we outline the emerging understanding of CAFs with a particular emphasis on their origin and heterogeneity, different mechanisms of their regulation, as well as their direct or indirect effect on immune cells that leads to immunosuppression.

scholarly journals Cancer-associated Fibroblasts: Origins, Heterogeneity and Functions in Tumor Microenvironment

2020 ◽  
Author(s):  
Kevin Dzobo
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Tumor Stroma ◽  
Bioinformatic Analysis ◽  
Therapy Resistance ◽  
Response To Therapy ◽  
The Cancer Genome Atlas ◽  
Cancer Associated Fibroblasts

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers’ expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients’ outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.

scholarly journals Potential Role of PDGFRβ-Associated THBS4 in Colorectal Cancer Development

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2533 ◽  
Author(s):  
Min Seob Kim ◽  
Hyun Seok Choi ◽  
Moxin Wu ◽  
JiYeon Myung ◽  
Eui Joong Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Tumor Microenvironment ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Tumor Development ◽  
Cancer Cell Line ◽  
Extracellular Matrix Protein ◽  
Mrna Levels ◽  
Invasion And Metastasis

Colorectal cancer is a significant cause of death since it frequently metastasizes to several organs such as the lung or liver. Tumor development is affected by various factors, including a tumor microenvironment, which may be an essential factor that leads to tumor growth, proliferation, invasion, and metastasis. In the tumor microenvironment, abnormal changes in various growth factors, enzymes, and cytokines can wield a strong influence on cancer. Thrombospondin-4 (THBS4), which is an extracellular matrix protein, also plays essential roles in the tumor microenvironment and mediates angiogenesis by transforming growth factor-β (TGFβ) signaling. Platelet-derived growth factor receptor β (PDGFRβ), which is a receptor tyrosine kinase and is also a downstream signal of TGFβ, is associated with invasion and metastasis in colorectal cancer. We identified that PDGFRβ and THBS4 are overexpressed in tumor tissues of colorectal cancer patients, and that PDGF-D expression increased after TGFβ treatment in the colon cancer cell line DLD-1. TGFβ and PDGF-D increased cellular THBS4 protein levels and secretion but did not increase THBS4 mRNA levels. This response was further confirmed by the inositol 1,4,5-triphosphate receptor (IP3R) and stromal interaction molecule 1 (STIM1) blockade as well as the PDGFRβ blockade. We propose that the PDGFRβ signal leads to a modification of the incomplete form of THBS4 to its complete form through IP3R, STIM1, and Ca2+-signal proteins, which further induces THBS4 secretion. Additionally, we identified that DLD-1 cell-conditioned medium stimulated with PDGF-D promotes adhesion, migration, and proliferation of colon myofibroblast CCD-18co cells, and this effect was intensified in the presence of thrombin. These findings suggest that excessive PDGFRβ signaling due to increased TGFβ and PDGF-D in colorectal tumors leads to over-secretion of THBS4 and proliferative tumor development.

Tumor microenvironment acid-sensitive liposomes enhanced colorectal cancer therapy by acting on both tumor cells and cancer-associated fibroblasts

Nanoscale ◽  
2021 ◽  
Author(s):  
chenglei li ◽  
Zhaohuan Li ◽  
Xue Gong ◽  
Jianhao Liu ◽  
Tingyue Zheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Tumor Cells ◽  
Crucial Role ◽  
Tumor Invasion ◽  
Cancer Associated Fibroblasts ◽  
Invasion And Metastasis ◽  
Promising Strategy

Cancer-associated fibroblasts (CAFs) play a crucial role in facilitating tumor invasion and metastasis, which act as the “soils” in tumor microenvironment (TME). Accordingly, it would be a promising strategy to...

scholarly journals The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2296
Author(s):  
Maurice Michel ◽  
Leonard Kaps ◽  
Annett Maderer ◽  
Peter R. Galle ◽  
Markus Moehler
Keyword(s):  
Colorectal Cancer ◽  
Stromal Cells ◽  
Tp53 Gene ◽  
Cancer Associated Fibroblasts ◽  
P53 Mutations ◽  
The One ◽  
Immunosuppressive Cells ◽  
And Personalized Medicine ◽  
Therapy Treatment

Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine.

scholarly journals Obesity-Related Fatty Acid and Cholesterol Metabolism in Cancer-Associated Host Cells

2020 ◽  
Vol 8 ◽  
Author(s):  
Ying Ye ◽  
Xiaoting Sun ◽  
Yongtian Lu
Keyword(s):  
Endothelial Cells ◽  
Fatty Acid ◽  
Tumor Microenvironment ◽  
Metabolic Regulation ◽  
Cholesterol Metabolism ◽  
Tumor Development ◽  
Host Cells ◽  
Acid Oxidation ◽  
Cancer Associated Fibroblasts ◽  
Future Perspectives

Obesity-derived disturbances in fatty acid and cholesterol metabolism are linked to numerous diseases, including various types of malignancy. In tumor cells, metabolic alterations have been long recognized and intensively studied. However, metabolic changes in host cells in the tumor microenvironment and their contribution to tumor development have been largely overlooked. During the last decade, research advances show that fatty acid oxidation, cholesterol metabolism, and lipid accumulation play critical roles in cancer-associated host cells such as endothelial cells, lymph endothelial cells, cancer-associated fibroblasts, tumor-associated myeloid cells, and tumor-associated lymphocytes. In addition to anti-angiogenic therapies and immunotherapy that have been practiced in the clinic, metabolic regulation is considered another promising cancer therapy targeting non-tumor host cells. Understanding the obesity-associated metabolism changes in cancer-associated host cells may ultimately be translated into therapeutic options that benefit cancer patients. In this mini-review, we briefly summarize the lipid metabolism associated with obesity and its role in host cells in the tumor microenvironment. We also discuss the current understanding of the molecular pathways involved and future perspectives to benefit from this metabolic complexity.

scholarly journals Breast Cancer CAFs: Spectrum of Phenotypes and Promising Targeting Avenues

2021 ◽  
Vol 22 (21) ◽  
pp. 11636
Author(s):  
Eiman Elwakeel ◽  
Andreas Weigert
Keyword(s):  
Breast Cancer ◽  
Stromal Cells ◽  
Tumor Development ◽  
Multiple Roles ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancer Therapy ◽  
Clinical Strategies ◽  
And Migration ◽  
Support Tumor Growth ◽  
Proliferation And Migration

Activation of the tumor-associated stroma to support tumor growth is a common feature observed in different cancer entities. This principle is exemplified by cancer-associated fibroblasts (CAFs), which are educated by the tumor to shape its development across all stages. CAFs can alter the extracellular matrix (ECM) and secrete a variety of different molecules. In that manner they have the capability to affect activation, survival, proliferation, and migration of other stromal cells and cancer cell themselves. Alteration of the ECM, desmoplasia, is a common feature of breast cancer, indicating a prominent role for CAFs in shaping tumor development in the mammary gland. In this review, we summarize the multiple roles CAFs play in mammary carcinoma. We discuss experimental and clinical strategies to interfere with CAFs function in breast cancer. Moreover, we highlight the issues arising from CAFs heterogeneity and the need for further research to identify CAFs subpopulation(s) that can be targeted to improve breast cancer therapy.

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