Cancer-Associated Fibroblasts Suppress Cancer Development: The Other Side of the Coin

Cancer-associated fibroblasts (CAFs) are the main stromal components of cancer, representing a group of heterogeneous cells. Many studies indicate that CAFs promote tumor development. Besides, evidence of the tumor suppression effects of CAFs keeps on merging. In the tumor microenvironment, multiple stimuli can activate fibroblasts. Notably, this does not necessarily mean the activated CAFs become strong tumor promoters immediately. The varying degree of CAFs activation makes quiescent CAFs, tumor-restraining CAFs, and tumor-promoting CAFs. Quiescent CAFs and tumor-restraining CAFs are more present in early-stage cancer, while comparatively, more tumor-promoting CAFs present in advanced-stage cancer. The underlying mechanism that balances tumor promotion or tumor inhibition effects of CAFs is mostly unknown. This review focus on the inhibitory effects of CAFs on cancer development. We describe the heterogeneous origin, markers, and metabolism in the CAFs population. Transgenetic mouse models that deplete CAFs or deplete CAFs activation signaling in the tumor stroma present direct evidence of CAFs protective effects against cancer. Moreover, we outline CAFs subpopulation and CAFs derived soluble factors that act as a tumor suppressor. Single-cell RNA-sequencing on CAFs population provides us new insight to classify CAFs subsets. Understanding the full picture of CAFs will help translate CAFs biology from bench to bedside and develop new strategies to improve precision cancer therapy.

Download Full-text

Macrophages reprogrammed by lung cancer microparticles promote tumor development via release of IL-1β

Cellular and Molecular Immunology ◽

10.1038/s41423-019-0313-2 ◽

2019 ◽

Vol 17 (12) ◽

pp. 1233-1244 ◽

Cited By ~ 3

Author(s):

Jie Chen ◽

Weiwei Sun ◽

Huafeng Zhang ◽

Jingwei Ma ◽

Pingwei Xu ◽

...

Keyword(s):

Lung Cancer ◽

Immune Cell ◽

Kinase Inhibitor ◽

Tumor Development ◽

Underlying Mechanism ◽

Promoting Effect ◽

Humanized Mouse Model ◽

Tumor Microenvironments ◽

Mutual Antagonism ◽

Promote Tumor Development

AbstractDespite their mutual antagonism, inflammation and immunosuppression coexist in tumor microenvironments due to tumor and immune cell interactions, but the underlying mechanism remains unclear. Previously, we showed that tumor cell-derived microparticles induce an M2 phenotype characterized by immunosuppression in tumor-infiltrating macrophages. Here, we further showed that lung cancer microparticles (L-MPs) induce macrophages to release a key proinflammatory cytokine, IL-1β, thus promoting lung cancer development. The underlying mechanism involves the activation of TLR3 and the NLRP3 inflammasome by L-MPs. More importantly, tyrosine kinase inhibitor treatment-induced L-MPs also induce human macrophages to release IL-1β, leading to a tumor-promoting effect in a humanized mouse model. These findings demonstrated that in addition to their anti-inflammatory effect, L-MPs induce a proinflammatory phenotype in tumor-infiltrating macrophages, promoting the development of inflammatory and immunosuppressive tumor microenvironments.

Download Full-text

Extracellular Matrix Biomarkers in Colorectal Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22179185 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9185

Author(s):

Min-Seob Kim ◽

Se-Eun Ha ◽

Moxin Wu ◽

Hannah Zogg ◽

Charles F. Ronkon ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Research ◽

Extracellular Matrix ◽

Tumor Microenvironment ◽

Tumor Development ◽

Tumor Stroma ◽

Cancer Development ◽

Invasion And Metastasis ◽

Protein Fibers ◽

Further Development

The cellular microenvironment composition and changes therein play an extremely important role in cancer development. Changes in the extracellular matrix (ECM), which constitutes a majority of the tumor stroma, significantly contribute to the development of the tumor microenvironment. These alterations within the ECM and formation of the tumor microenvironment ultimately lead to tumor development, invasion, and metastasis. The ECM is composed of various molecules such as collagen, elastin, laminin, fibronectin, and the MMPs that cleave these protein fibers and play a central role in tissue remodeling. When healthy cells undergo an insult like DNA damage and become cancerous, if the ECM does not support these neoplastic cells, further development, invasion, and metastasis fail to occur. Therefore, ECM-related cancer research is indispensable, and ECM components can be useful biomarkers as well as therapeutic targets. Colorectal cancer specifically, is also affected by the ECM and many studies have been conducted to unravel the complex association between the two. Here we summarize the importance of several ECM components in colorectal cancer as well as their potential roles as biomarkers.

Download Full-text

Cancer-associated fibroblasts promote the survival of irradiated nasopharyngeal carcinoma cells via the NF-κB pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01878-x ◽

2021 ◽

Vol 40 (1) ◽

Cited By ~ 1

Author(s):

Weiqiang Huang ◽

Longshan Zhang ◽

Mi Yang ◽

Xixi Wu ◽

Xiaoqing Wang ◽

...

Keyword(s):

Dna Damage ◽

Nasopharyngeal Carcinoma ◽

Enrichment Analysis ◽

Underlying Mechanism ◽

Gene Set Enrichment Analysis ◽

Cancer Associated Fibroblasts ◽

Western Blot Assay ◽

Damage Level ◽

Radiation Resistant

Abstract Background Irradiation has emerged as a valid tool for nasopharyngeal carcinoma (NPC) in situ treatment; however, NPC derived from tissues treated with irradiation is a main cause cancer-related death. The purpose of this study is to uncover the underlying mechanism regarding tumor growth after irradiation and provided potential therapeutic strategy. Methods Fibroblasts were extracted from fresh NPC tissue and normal nasopharyngeal mucosa. Immunohistochemistry was conducted to measure the expression of α-SMA and FAP. Cytokines were detected by protein array chip and identified by real-time PCR. CCK-8 assay was used to detect cell proliferation. Radiation-resistant (IRR) 5-8F cell line was established and colony assay was performed to evaluate tumor cell growth after irradiation. Signaling pathways were acquired via gene set enrichment analysis (GSEA). Comet assay and γ-H2AX foci assay were used to measure DNA damage level. Protein expression was detected by western blot assay. In vivo experiment was performed subcutaneously. Results We found that radiation-resistant NPC tissues were constantly infiltrated with a greater number of cancer-associated fibroblasts (CAFs) compared to radiosensitive NPC tissues. Further research revealed that CAFs induced the formation of radioresistance and promoted NPC cell survival following irradiation via the IL-8/NF-κB pathway to reduce irradiation-induced DNA damage. Treatment with Tranilast, a CAF inhibitor, restricted the survival of CAF-induced NPC cells and attenuated the of radioresistance properties. Conclusions Together, these data demonstrate that CAFs can promote the survival of irradiated NPC cells via the NF-κB pathway and induce radioresistance that can be interrupted by Tranilast, suggesting the potential value of Tranilast in sensitizing NPC cells to irradiation.

Download Full-text

UVB protective effects of Sargassum horneri through the regulation of Nrf2 mediated antioxidant mechanism

Scientific Reports ◽

10.1038/s41598-021-88949-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eui Jeong Han ◽

Seo-Young Kim ◽

Hee-Jin Han ◽

Hyun-Soo Kim ◽

Kil-Nam Kim ◽

...

Keyword(s):

Skin Barrier ◽

Human Keratinocytes ◽

Underlying Mechanism ◽

Ultraviolet B ◽

Sargassum Horneri ◽

Cellular Damage ◽

Protective Effects ◽

Skin Damage ◽

Antioxidant Mechanism ◽

Induced Apoptosis

AbstractThe present study aimed to evaluate the protective effect of a methanol extract of Sargassum horneri (SHM), which contains 6-hydroxy-4,4,7a-trimethyl-5,6,7,7a-tetrahydrobenzofuran-2(4H)-one (HTT) and apo-9′-fucoxanthinone, against ultraviolet B (UVB)-induced cellular damage in human keratinocytes and its underlying mechanism. SHM significantly improved cell viability of UVB-exposed human keratinocytes by reducing the generation of intracellular reactive oxygen species (ROS). Moreover, SHM inhibited UVB exposure-induced apoptosis by reducing the formation of apoptotic bodies and the populations of the sub-G1 hypodiploid cells and the early apoptotic cells by modulating the expression of the anti- and pro-apoptotic molecules, Bcl-2 and Bax, respectively. Furthermore, SHM inhibited NF-κB p65 activation by inducing the activation of Nrf2/HO-1 signaling. The cytoprotective and antiapoptotic activities of SHM are abolished by the inhibition of HO-1 signaling. In further study, SHM restored the skin dryness and skin barrier disruption in UVB-exposed human keratinocytes. Based to these results, our study suggests that SHM protects the cells against UVB-induced cellular damages through the Nrf2/HO-1/NF-κB p65 signaling pathway and may be potentially useful for the prevention of UVB-induced skin damage.

Download Full-text

Dynamic Stromal Alterations Influence Tumor-Stroma Crosstalk to Promote Pancreatic Cancer and Treatment Resistance

Cancers ◽

10.3390/cancers13143481 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3481

Author(s):

Kendelle J. Murphy ◽

Cecilia R. Chambers ◽

David Herrmann ◽

Paul Timpson ◽

Brooke A. Pereira

Keyword(s):

Pancreatic Cancer ◽

Tumor Development ◽

Treatment Resistance ◽

Tumor Stroma ◽

Response To Treatment ◽

Ductal Adenocarcinoma ◽

Cell Phenotype ◽

Stromal Compartment ◽

Clinical Prognosis ◽

Functional Value

Many cancer studies now recognize that disease initiation, progression, and response to treatment are strongly influenced by the microenvironmental niche. Widespread desmoplasia, or fibrosis, is fundamental to pancreatic cancer development, growth, metastasis, and treatment resistance. This fibrotic landscape is largely regulated by cancer-associated fibroblasts (CAFs), which deposit and remodel extracellular matrix (ECM) in the tumor microenvironment (TME). This review will explore the prognostic and functional value of the stromal compartment in predicting outcomes and clinical prognosis in pancreatic ductal adenocarcinoma (PDAC). We will also discuss the major dynamic stromal alterations that occur in the pancreatic TME during tumor development and progression, and how the stromal ECM can influence cancer cell phenotype, metabolism, and immune response from a biochemical and biomechanical viewpoint. Lastly, we will provide an outlook on the latest clinical advances in the field of anti-fibrotic co-targeting in combination with chemotherapy or immunotherapy in PDAC, providing insight into the current challenges in treating this highly aggressive, fibrotic malignancy.

Download Full-text

Favorable Effects of GLP-1 Receptor Agonist against Pancreatic β-Cell Glucose Toxicity and the Development of Arteriosclerosis: “The Earlier, the Better” in Therapy with Incretin-Based Medicine

International Journal of Molecular Sciences ◽

10.3390/ijms22157917 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7917

Author(s):

Hideaki Kaneto ◽

Tomohiko Kimura ◽

Masashi Shimoda ◽

Atsushi Obata ◽

Junpei Sanada ◽

...

Keyword(s):

Large Scale ◽

Cell Function ◽

Apoptotic Cell ◽

Early Stage ◽

Insulin Biosynthesis ◽

Protective Effects ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Glucose Toxicity

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

Download Full-text

Early Detection and Dynamic Changes of Circulating Tumor Cells in Transgenic NeuN Transgenic (NTTg) Mice with Spontaneous Breast Tumor Development

Cancers ◽

10.3390/cancers13133294 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3294

Author(s):

Wen-Sy Tsai ◽

Tsung-Fu Hung ◽

Jia-Yang Chen ◽

Shu-Huan Huang ◽

Ying-Chih Chang

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Breast Tumor ◽

Early Stage ◽

Tumor Development ◽

P Value ◽

Vascular Density ◽

Dynamic Changes ◽

Tumor Bearing ◽

Development Methods

Background: This study used NeuN transgenic (NTTg) mice with spontaneous breast tumor development to evaluate the dynamic changes of circulating tumor cells (CTCs) prior to and during tumor development. Methods: In this longitudinal, clinically uninterrupted study, we collected 75 μL of peripheral blood at the age of 8, 12, 16, and 20 weeks in the first group of five mice, and at the age of 32 weeks, the time of tumor palpability, and one week after tumor palpability in the second group of four mice. Diluted blood samples were run through a modified mouse-CMx chip to isolate the CTCs. Results: The CTC counts of the first group of mice were low (1 ± 1.6) initially. The average CTC counts were 16 ± 9.5, 29.0 ± 18.2, and 70.0 ± 30.3 cells per 75 μL blood at the age of 32 weeks, the time of tumor palpability, and one week after tumor palpability, respectively. There was a significant positive correlation between an increase in CTC levels and tumor vascular density (p-value < 0.01). This correlation was stronger than that between CTC levels and tumor size (p-value = 0.076). The captured CTCs were implanted into a non-tumor-bearing NTTg mouse for xenografting, confirming their viability and tumorigenesis. Conclusion: Serial CTCs during an early stage of tumor progression were quantified and found to be positively correlated with the later tumor vascular density and size. Furthermore, the successful generation of CTC-derived xenografts indicates the tumorigenicity of this early onset CTC population.

Download Full-text

The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13153740 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3740

Author(s):

Chunye Zhang ◽

Ming Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Fatty Liver ◽

Early Stage ◽

Primary Liver Cancer ◽

Treatment Options ◽

Underlying Mechanism ◽

Diagnostic Methods ◽

T Cell Therapy ◽

Nonalcoholic Fatty Liver

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, followed by cholangiocarcinoma (CCA). HCC is the third most common cause of cancer death worldwide, and its incidence is rising, associated with an increased prevalence of obesity and nonalcoholic fatty liver disease (NAFLD). However, current treatment options are limited. Genetic factors and epigenetic factors, influenced by age and environment, significantly impact the initiation and progression of NAFLD-related HCC. In addition, both transcriptional factors and post-transcriptional modification are critically important for the development of HCC in the fatty liver under inflammatory and fibrotic conditions. The early diagnosis of liver cancer predicts curative treatment and longer survival. However, clinical HCC cases are commonly found in a very late stage due to the asymptomatic nature of the early stage of NAFLD-related HCC. The development of diagnostic methods and novel biomarkers, as well as the combined evaluation algorithm and artificial intelligence, support the early and precise diagnosis of NAFLD-related HCC, and timely monitoring during its progression. Treatment options for HCC and NAFLD-related HCC include immunotherapy, CAR T cell therapy, peptide treatment, bariatric surgery, anti-fibrotic treatment, and so on. Overall, the incidence of NAFLD-related HCC is increasing, and a better understanding of the underlying mechanism implicated in the progression of NAFLD-related HCC is essential for improving treatment and prognosis.

Download Full-text

Mesenchymal stromal cells promote tumor development and progression

Cytotherapy ◽

10.1016/j.jcyt.2015.03.424 ◽

2015 ◽

Vol 17 (6) ◽

pp. S36

Author(s):

Gyeongsin Park ◽

Byunghoo Song ◽

Kyo Young Song ◽

Yang-Guk Chung ◽

Youn-Soo Lee

Keyword(s):

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Tumor Development ◽

Promote Tumor Development

Download Full-text

Short-Term High Fat Intake Does Not Significantly Alter Markers of Renal Function or Inflammation in Young Male Sprague-Dawley Rats

Journal of Nutrition and Metabolism ◽

10.1155/2015/157520 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Catherine Crinigan ◽

Matthew Calhoun ◽

Karen L. Sweazea

Keyword(s):

Kidney Disease ◽

Renal Mass ◽

Early Stage ◽

Young Male ◽

Protective Effects ◽

Sprague Dawley ◽

High Fat ◽

Short Term ◽

Sprague Dawley Rats ◽

The Impact

Chronic high fat feeding is correlated with diabetes and kidney disease. However, the impact of short-term high fat diets (HFD) is not well-understood. Six weeks of HFD result in indices of metabolic syndrome (increased adiposity, hyperglycemia, hyperinsulinemia, hyperlipidemia, hyperleptinemia, and impaired endothelium-dependent vasodilation) compared to rats fed on standard chow. The hypothesis was that short-term HFD would induce early signs of renal disease. Young male Sprague-Dawley rats were fed either HFD (60% fat) or standard chow (5% fat) for six weeks. Morphology was determined by measuring changes in renal mass and microstructure. Kidney function was measured by analyzing urinary protein, creatinine, and hydrogen peroxide (H2O2) concentrations, as well as plasma cystatin C concentrations. Renal damage was measured through assessment of urinary oxDNA/RNA concentrations as well as renal lipid peroxidation, tumor necrosis factor alpha (TNFα), and interleukin 6 (IL-6). Despite HFD significantly increasing adiposity and renal mass, there was no evidence of early stage kidney disease as measured by changes in urinary and plasma biomarkers as well as histology. These findings suggest that moderate hyperglycemia and inflammation produced by short-term HFD are not sufficient to damage kidneys or that the ketogenic HFD may have protective effects within the kidneys.

Download Full-text