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.

Abstract 348: Development of an RNA based diagnostic panel to the tumor microenvironment to match cancer therapies for colorectal cancer

2021 ◽  
Author(s):  
Kristen Strand-Tibbitts ◽  
Kerry Culm-Merdek ◽  
Valerie Chamberlain Santps ◽  
Laura Benjamin ◽  
Julia Carter ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Therapies ◽  
Diagnostic Panel

scholarly journals Stemness-Attenuating miR-503-3p as a Paracrine Factor to Regulate Growth of Cancer Stem Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Minkoo Seo ◽  
Seung Min Kim ◽  
Eun Young Woo ◽  
Ki-Cheol Han ◽  
Eun Joo Park ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Growth ◽  
Cellular Heterogeneity ◽  
Paracrine Factor ◽  
Adipose Stem Cell ◽  
Self Renewal ◽  
Human Adipose Stem Cell ◽  
Pluripotency Genes

Cancer stem cells (CSCs) with self-renewal abilities endorse cellular heterogeneity, resulting in metastasis and recurrence. However, there are no promising therapeutics directed against CSCs. Herein, we found that miR-503-3p inhibited tumor growth via the regulation of CSC proliferation and self-renewal. miR-503-3p, isolated from human adipose stem cell- (ASC-) derived exosomes, suppressed initiation and progression of CSCs as determined by anchorage-dependent (colony formation) and anchorage-independent (tumorsphere formation) assays. The expression of pluripotency genes was significantly decreased in miR-503-3p-treated CSCs. Furthermore, xenografts, which received miR-503-3p, exhibited remarkably reduced tumor growth in vivo. Thus, miR-503-3p may function as a stemness-attenuating factor via cell-to-cell communications.

scholarly journals A novel BMI-1 inhibitor QW24 for the treatment of stem-like colorectal cancer

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Jinhua Wang ◽  
Yajing Xing ◽  
Yingying Wang ◽  
Yundong He ◽  
Liting Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Liver Metastasis ◽  
Tumor Growth ◽  
Cell Lines ◽  
Xenograft Model ◽  
Proliferation Assay ◽  
Self Renewal ◽  
Metastasis Model

Abstract Background Cancer-initiating cell (CIC), a functionally homogeneous stem-like cell population, is resonsible for driving the tumor maintenance and metastasis, and is a source of chemotherapy and radiation-therapy resistance within tumors. Targeting CICs self-renewal has been proposed as a therapeutic goal and an effective approach to control tumor growth. BMI-1, a critical regulator of self-renewal in the maintenance of CICs, is identified as a potential target for colorectal cancer therapy. Methods Colorectal cancer stem-like cell lines HCT116 and HT29 were used for screening more than 500 synthetic compounds by sulforhodamine B (SRB) cell proliferation assay. The candidate compound was studied in vitro by SRB cell proliferation assay, western blotting, cell colony formation assay, quantitative real-time PCR, flow cytometry analysis, and transwell migration assay. Sphere formation assay and limiting dilution analysis (LDA) were performed for measuring the effect of compound on stemness properties. In vivo subcutaneous tumor growth xenograft model and liver metastasis model were performed to test the efficacy of the compound treatment. Student’s t test was applied for statistical analysis. Results We report the development and characterization of a small molecule inhibitor QW24 against BMI-1. QW24 potently down-regulates BMI-1 protein level through autophagy-lysosome degradation pathway without affecting the BMI-1 mRNA level. Moreover, QW24 significantly inhibits the self-renewal of colorectal CICs in stem-like colorectal cancer cell lines, resulting in the abrogation of their proliferation and metastasis. Notably, QW24 significantly suppresses the colorectal tumor growth without obvious toxicity in the subcutaneous xenograft model, as well as decreases the tumor metastasis and increases mice survival in the liver metastasis model. Moreover, QW24 exerts a better efficiency than the previously reported BMI-1 inhibitor PTC-209. Conclusions Our preclinical data show that QW24 exerts potent anti-tumor activity by down-regulating BMI-1 and abrogating colorectal CICs self-renewal without obvious toxicity in vivo, suggesting that QW24 could potentially be used as an effective therapeutic agent for clinical colorectal cancer treatment.

scholarly journals Bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signaling pathway

2021 ◽  
Author(s):  
Ke Xu ◽  
Kai Fang ◽  
Yueping Zhan ◽  
Yuqian Wang ◽  
Chengqi Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Signaling Pathway ◽  
Umbilical Vein ◽  
Tumour Microenvironment ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background Anti-angiogenesis therapy has increasingly become an important strategy for the treatment of colorectal cancer. Recent studies have shown that tumor microenvironment (TME) promotes tumour angiogenesis. Bufalin is an active compound whose anti-tumor efficacy has been proven by previous studies. However, there are very few studies on the anti-angiogenic effects of bufalin. Methods Herein, human umbilical vein endothelial cells (HUVEC) tube formation, migration and adhesion test were used to assess angiogenesis in vitro. Western blot and quantitative PCR were used to detect relevant protein levels and the expressions of mRNAs. Subcutaneous xenograft tumor model and hepatic metastasis model in mice were established to investigate the influence of bufalin on angiogenesis-mediated by TME in vivo. Results We found that the angiogenesis mediated by tumor microenvironment cells was significantly inhibited in the present of bufalin. The results demonstrated that the pro-angiogenic gene in HUVEC such as VEGF, PDGFA, E-selectin and P-selectin were downregulated by bufalin, and the downregulation was regulated by inhibiting the STAT3 pathway. Overexpression STAT3 could reverse the inhibitory effect of bufalin on angiogenesis. What is more, few reduction of angiogenesis when bufalin directly acted on tumor microenvironment cells. Conclusion Our findings demonstrate that bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signaling pathway of vascular endothelial cells, which reveals that bufalin may be used as a new anti-angiogenic adjuvant therapy medicine in the treatment of colorectal cancer.

scholarly journals Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 462 ◽  
Author(s):  
Kevin Chih-Yang Huang ◽  
Shu-Fen Chiang ◽  
William Tzu-Liang Chen ◽  
Tsung-Wei Chen ◽  
Ching-Han Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Efficacy ◽  
Dna Methyltransferase ◽  
Chemotherapeutic Agents ◽  
Dna Hypomethylation ◽  
Chemotherapeutic Regimen ◽  
Response To Chemotherapy ◽  
Clinical Benefits

Programmed cell death-1 (PD-1) has demonstrated impressive clinical outcomes in several malignancies, but its therapeutic efficacy in the majority of colorectal cancers is still low. Therefore, methods to improve its therapeutic efficacy in colorectal cancer (CRC) patients need further investigation. Here, we demonstrate that immunogenic chemotherapeutic agents trigger the induction of tumor PD-L1 expression in vitro and in vivo, a fact which was validated in metastatic CRC patients who received preoperatively neoadjuvant chemotherapy (neoCT) treatment, suggesting that tumor PD-L1 upregulation by chemotherapeutic regimen is more feasible via PD-1/PD-L1 immunotherapy. However, we found that the epigenetic control of tumor PD-L1 via DNA methyltransferase 1 (DNMT1) significantly influenced the response to chemotherapy. We demonstrate that decitabine (DAC) induces DNA hypomethylation, which not only directly enhances tumor PD-L1 expression but also increases the expression of immune-related genes and intratumoral T cell infiltration in vitro and in vivo. DAC was found to profoundly enhance the therapeutic efficacy of PD-L1 immunotherapy to inhibit tumor growth and prolong survival in vivo. Therefore, it can be seen that DAC remodels the tumor microenvironment to improve the effect of PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger anti-cancer immune responses, providing potential clinical benefits to CRC patients in the future.

In vivo real-time imaging of tumor microcirculatory alterations in colorectal liver metastatic xenografts by chemotherapy using multiphoton microscopy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21053-e21053
Author(s):  
Koji Tanaka ◽  
Masato Okigami ◽  
Yuji Toiyama ◽  
Yuhki Morimoto ◽  
Kohei Matsushita ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Blood Flow ◽  
Liver Metastasis ◽  
Tumor Microenvironment ◽  
Real Time ◽  
Fluorescent Protein ◽  
Tumor Vessels ◽  
Tumor Endothelium ◽  
Tumor Microcirculation

e21053 Background: Tumor endothelium is a distinct target for anticancer treatments of metastatic colorectal cancer. Various chemotherapeutics themselves have anti-angiogenic effects on tumor microenvironment by targeting proliferative endothelial cells during tumor angiogenesis. In this study, we imaged the dynamics of tumor microcirculation of colorectal liver metastasis in living mice in vivo real-time using two-photon laser scanning microscopy (TPLSM), and evaluated the microcirculatory alterations in tumor microenvironment by chemotherapy. Methods: Red fluorescent protein expressing human colorectal cancer cell line (HT29) was inoculated to the spleen of green fluorescent protein expressing nude mice. 5-fluorouracil or irinotecan was administered three times a week for more than three weeks for metronomic scheduling. Intravital TPLSM was performed at multiple time points for time-series imaging of liver metastatic xenografts in the same mice. The alterations in tumor microcirculation during chemotherapy was evaluated by measuring blood flows at tumor vessels of colorectal liver metastasis and hepatic sinusoids of adjacent normal liver. Results: At the first TPLSM imaging, the blood flow, as determined from the movement of platelets, was heterogeneous and non-directional in the tumor vessels of liver metastatic xenografts. The blood flow was relatively slower in tumor vessels than normal hepatic sinusoids. At the second TPLSM imaging after chemotherapy, platelet aggregation was observed in tumor vessels of the same mice. Aggregated platelets were frequently adhered to the tumor endothelium, suggesting tumor vessel damage or intratumoral coagulation abnormality by chemotherapy. There was no difference in chemotherapeutics with regard to these findings. Conclusions: Intravital TPLSM imaging of tumor microcirculation at metastatic tumor xenografts is a useful tool to evaluate anti-angiogenic drugs in preclinical models.

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 Cyclodextrin-based host-guest complexes loaded with regorafenib for colorectal cancer treatment

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hongzhen Bai ◽  
Jianwei Wang ◽  
Chi Uyen Phan ◽  
Qi Chen ◽  
Xiurong Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cell Proliferation ◽  
Therapeutic Targeting ◽  
Potential Strategy ◽  
Colorectal Cancer Treatment ◽  
Channel Type

AbstractThe malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG’s anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.

scholarly journals Metabolic Relationship Between Cancer-Associated Fibroblasts and Cancer Cells

2021 ◽  
pp. 189-204 ◽  
Author(s):  
Christos Sazeides ◽  
Anne Le
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cell Interactions ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblasts ◽  
Physical Support ◽  
Activated State ◽  
Cancer Initiation ◽  
New Cancer Therapies ◽  
The Way

AbstractCancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME), play an important role in cancer initiation, progression, and metastasis. Recent findings have demonstrated that the TME not only provides physical support for cancer cells but also directs cell-to-cell interactions (in this case, the interaction between cancer cells and CAFs). As cancer progresses, the CAFs also coevolve, transitioning from an inactivated state to an activated state. The elucidation and understanding of the interaction between cancer cells and CAFs will pave the way for new cancer therapies [1–3].

scholarly journals Cancer-Associated Fibroblasts Promote the Upregulation of PD-L1 Expression Through Akt Phosphorylation in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yang Gao ◽  
Zhao Sun ◽  
Junjie Gu ◽  
Zhe Li ◽  
Xiuxiu Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Molecular Mechanisms ◽  
Immune Escape ◽  
Disease Free Survival ◽  
Epithelial Tissue ◽  
Cancer Associated Fibroblasts ◽  
Tumor Immune Escape ◽  
Akt Phosphorylation

Upregulation of immune checkpoint proteins is one of the main mechanisms for tumor immune escape. The expression of programmed death ligand-1 (PD-L1) in colorectal cancer (CRC) is higher than in normal colorectal epithelial tissue, and patients with higher PD-L1 expression have a poorer prognosis. Additionally, PD-L1 expression in CRC is affected by the tumor microenvironment (TME). As a major component of the TME, cancer-associated fibroblasts (CAFs) can act as immune regulators and generate an immunosuppressive tumor microenvironment. Therefore, we speculated that CAFs may be related to the upregulation of PD-L1 in CRC, which leads to tumor immune escape. We found that CAFs upregulate PD-L1 expression in CRC cells through AKT phosphorylation, thereby reducing the killing of CRC cells by peripheral blood mononuclear cells. The ratio of CAFs to CRC cells was positively correlated with AKT phosphorylation and the expression of PD-L1 in CRC in vitro. Consistent with the in vitro results, high CAF content and high expression of PD-L1 were negatively correlated with disease-free survival (DFS) of CRC patients. These results indicate that the upregulation of PD-L1 expression in CRC by CAFs through the activation of Akt is one of the molecular mechanisms of tumor immune escape. Thus, targeted anti-CAF therapy may help improve the efficacy of immunotherapy.

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