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

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.

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TNF-alpha Induces Pro-Inflammatory Factors in Colorectal Cancer Microenvironment

Medical Science and Discovery ◽

10.36472/msd.v7i4.368 ◽

2020 ◽

Vol 7 (4) ◽

pp. 466-469

Author(s):

Ahu Pakdemirli ◽

Gizem Calibasi Kocal

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Interleukin 6 ◽

Interleukin 8 ◽

Soluble Factors ◽

Tnf Α ◽

Colorectal Cancer Cells ◽

Cancer Tumor ◽

Cellular Components

Objective: The tumor microenvironment has a crucial role in organizing cancer malignancy, progression, drug resistance and survival. It consists of cellular and non-cellular components. These non-cellular components such as cytokines, extracellular matrix, growth factors and metabolites are responsible for shifting the action from pro-cancer to anti-cancer effects. Twenty percent of all cancers occur in association with chronic inflammation via cytokines. Even cancers that are not caused by chronic inflammation, present high levels of cytokine expression pattern in their tumor microenvironment. Tumor necrosis factor-alpha (TNF-α) and some interleukins are characterized as pro-tumorigenic cytokines and they were involved in cancer by presenting their ability to activate the oncogenic transcription factors. The aim of this study is to evaluate the remodeling of colorectal cancer tumor microenvironment by TNF-α. Material and Methods: TNF-α (5ng/ml) was applied to HT-29 colorectal cancer cells, then human soluble factors were determined by using Human Cytokine Group 1, 8 plex Panel (Bio-Rad Laboratories Inc. USA) and Magpix Luminex instrument and xPONENT software (version 4.2, Luminex Corp, Austin, Texas, US). The results were normalized to total protein concentration estimated via Bradford assay. Results: Current research highlights the effect of TNF-α on the tumor microenvironment. Interleukin-6 and interleukin -8 soluble factors were higher in TNF-α treated colorectal cancer cells when compared with untreated control group. Conclusion: The results of the study show that TNF-α is responsible for elevating the levels of interleukin-6 and interleukin-8, which are associated with inflammation in the tumor microenvironment. Key words: Colorectal Cancer, Tumor Microenvironment, Cytokines, TNF-α, Interleukin-6, interleukin -8

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miRNAs derived from cancer-associated fibroblasts in colorectal cancer

Epigenomics ◽

10.2217/epi-2019-0110 ◽

2019 ◽

Vol 11 (14) ◽

pp. 1627-1645 ◽

Cited By ~ 23

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.

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Exosomal miRNAs and lncRNAs: The Modulator Keys of Cancer-Associated Fibroblasts in the Genesis and Progression of Malignant Neoplasms

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.717478 ◽

2021 ◽

Vol 9 ◽

Author(s):

Julio César Villegas-Pineda ◽

Mélida del Rosario Lizarazo-Taborda ◽

Adrián Ramírez-de-Arellano ◽

Ana Laura Pereira-Suárez

Keyword(s):

Tumor Microenvironment ◽

Epithelial Mesenchymal Transition ◽

Future Perspective ◽

Malignant Neoplasms ◽

Cancer Associated Fibroblasts ◽

Mesenchymal Transition ◽

Relevant Evidence ◽

State Of Research ◽

Therapeutic Tools ◽

Cellular Components

The tumor microenvironment is made up of a universe of molecular and cellular components that promote or inhibit the development of neoplasms. Among the molecular elements are cytokines, metalloproteinases, proteins, mitochondrial DNA, and nucleic acids, within which the ncRNAs: miRNAs and lncRNAs stand out due to their direct modulating effects on the genesis and progression of various cancers. Regarding cellular elements, the solid tumor microenvironment is made up of tumor cells, healthy adjacent epithelial cells, immune system cells, endothelial cells, and stromal cells, such as cancer-associated fibroblasts, which are capable of generating a modulating communication network with the other components of the tumor microenvironment through, among other mechanisms, the secretion of exosomal vesicles loaded with miRNAs and lncRNAs. These ncRNAs are key pieces in developing neoplasms since they have diverse effects on cancer cells and healthy cells, favoring or negatively regulating protumoral cellular events, such as migration, invasion, proliferation, metastasis, epithelial-mesenchymal transition, and resistance to treatment. Due to the growing number of relevant evidence in recent years, this work focused on reviewing, analyzing, highlighting, and showing the current state of research on exosomal ncRNAs derived from cancer-associated fibroblasts and their effects on different neoplasms. A future perspective on using these ncRNAs as real therapeutic tools in the treatment of cancer patients is also proposed.

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Chemokines—What Is Their Role in Colorectal Cancer?

Cancer Control ◽

10.1177/1073274820903384 ◽

2020 ◽

Vol 27 (1) ◽

pp. 107327482090338 ◽

Cited By ~ 2

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.

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Cancer-associated fibroblasts as key regulators of the breast cancer tumor microenvironment

Cancer and Metastasis Reviews ◽

10.1007/s10555-018-9768-3 ◽

2018 ◽

Vol 37 (4) ◽

pp. 577-597 ◽

Cited By ~ 35

Author(s):

J. M. Houthuijzen ◽

J. Jonkers

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Cancer Associated Fibroblasts ◽

Cancer Tumor

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Mesenchymal Stromal-Like Cells in the Glioma Microenvironment: What Are These Cells?

Cancers ◽

10.3390/cancers12092628 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2628

Author(s):

Anne Clavreul ◽

Philippe Menei

Keyword(s):

Blood Vessels ◽

Immune Cells ◽

Stromal Cells ◽

Low Ph ◽

Cancer Associated Fibroblasts ◽

Tumor Resistance ◽

Interstitial Pressure ◽

Close Proximity ◽

Cellular Components ◽

Glioma Microenvironment

The glioma microenvironment is a critical regulator of tumor progression. It contains different cellular components such as blood vessels, immune cells, and neuroglial cells. It also contains non-cellular components, such as the extracellular matrix, extracellular vesicles, and cytokines, and has certain physicochemical properties, such as low pH, hypoxia, elevated interstitial pressure, and impaired perfusion. This review focuses on a particular type of cells recently identified in the glioma microenvironment: glioma-associated stromal cells (GASCs). This is just one of a number of names given to these mesenchymal stromal-like cells, which have phenotypic and functional properties similar to those of mesenchymal stem cells and cancer-associated fibroblasts. Their close proximity to blood vessels may provide a permissive environment, facilitating angiogenesis, invasion, and tumor growth. Additional studies are required to characterize these cells further and to analyze their role in tumor resistance and recurrence.

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

Journal of Experimental Medicine ◽

10.1084/jem.20131195 ◽

2013 ◽

Vol 210 (13) ◽

pp. 2851-2872 ◽

Cited By ~ 165

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.671595 ◽

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.

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

10.20944/preprints202001.0155.v1 ◽

2020 ◽

Cited By ~ 1

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.

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