Significant co-expression of putative cancer stem cell markers, EpCAM and CD166, correlates with tumor stage and invasive behavior in colorectal cancer

Background The crucial oncogenic role of cancer stem cells (CSCs) in tumor maintenance, progression, drug resistance, and relapse has been clarified in different cancers, particularly in colorectal cancer (CRC). The current study was conducted to evaluate the co-expression pattern and clinical significance of epithelial cell adhesion molecules (EpCAM) and activated leukocyte cell adhesion (CD166 or ALCAM) in CRC patients. Methods This study was carried out on 458 paraffin-embedded CRC specimens by immunohistochemistry on tissue microarray (TMA) slides. Results Elevated expression of EpCAM and CD166 was observed in 61.5% (246/427) and 40.5% (164/405) of CRC cases. Our analysis showed a significant positive association of EpCAM expression with tumor size (P = 0.02), tumor stage (P = 0.007), tumor differentiate (P = 0.005), vascular (P = 0.01), neural (P = 0.01), and lymph node (P = 0.001) invasion. There were no significant differences between CD166 expression and clinicopathological parameters. Moreover, the combined analysis demonstrated a reciprocal significant correlation between EpCAM and CD166 expression (P = 0.02). Interestingly, there was a significant positive correlation between EpCAM/CD166 phenotypes expression and tumor stage (P = 0.03), tumor differentiation (P = 0.05), neural, and lymph node invasion (P =0.01). Conclusions The significant correlation of EpCAM and CD166 expression and their association with tumor progression and aggressive behavior is the reason for the suggestion of these two CSC markers as promising targets to promote novel effective targeted-therapy strategies for cancer treatment in the present study.

Cancer stem cells and their detection using specific cancer stem cell markers- a new strategy for cancer therapies

Background: In the previous theories of cancer, they considered that cancer was a homogeneous which mean that the tumor had only tumor cells and for this reason the treatment for any tumor directed to kill these tumor cells. But, with rising of the metastatic cases of cancer patients, another theory have been raised, that the cancer is a heterogeneous disease which composed of tumor cells that previously the chemotherapy and other cancer therapies directed toward them, in addition there is another group of cells, called cancer stem cells (CSCs), these are more aggressive than the tumor cells that can force the poor microenvironment of the cancer tissue and survive and also they are undifferentiated cells so can undergo mitosis to produce more tumor cells and another group of cancer stem cells in contrast to the tumor cells, which considered a post mitotic and not divided. Objective: Demonstrate some of cancer stem cell markers that considered an important indicators of early cancer development and lately to detect cases of metastasis. Conclusion: The theory of the presence of cancer stem cells is more acceptable and applicable and so the cancer therapy must be directed to these groups of cancer stem cells.

CARMA3 Promotes Colorectal Cancer Cell Motility and Cancer Stemness via YAP-Mediated NF-κB Activation

CARD-recruited membrane-associated protein 3 (CARMA3) is overexpressed in various cancers and is associated with cancer cell proliferation, metastasis, and tumor progression; however, the underlying mechanisms of CARMA3 in colorectal cancer (CRC) metastasis remain unclear. Here, we found that higher CARMA3 expression was correlated with poor overall survival and metastasis in CRC patients from the TNMplot database and Human Tissue Microarray staining. Elevating CARMA3 expression promoted cell proliferation, epithelial-mesenchymal transition (EMT) induction, migration/invasion abilities, sphere formation, and cancer stem cell markers expression. Knockdown of CARMA3 decreased these processes via the EMT-related transcription factor Slug. Moreover, CARMA3 depletion significantly reduced tumor growth in mice that were consistent with the in vitro results. CRC migration/invasion could be regulated by CARMA3/YAP/Slug signaling axis using genetic inhibition of Yes-associated protein (YAP). Interestingly, CARMA3 induced activation of nuclear factor (NF)-κB through YAP expression, contributing to upregulation of Slug. YAP expression positively correlated with CARMA3, NF-κB, and Slug gene expression and poor clinical outcomes in CRC patients. Our findings demonstrate for the first time that CARMA3 plays an important role in CRC progression, which may serve as a potential diagnostic biomarker and candidate therapeutic target for CRC treatment.

Cancer-Associated Fibroblasts Regulate the Plasticity of Breast Cancer Stemness through the Production of Leukemia Inhibitory Factor

Leukemia inhibitory factor (LIF), as a member of the interleukin-6 cytokine family, plays a complex role in solid tumors. However, the effect of LIF as a tumor microenvironment factor on plasticity control in breast cancer remains largely unknown. In this study, an in vitro investigation is conducted to determine the crosstalk between breast cancer cells and fibroblasts. Based on the results, cancer-associated fibroblasts are producers of LIF in the cocultivation system with breast cancer cells. Treatment with the CAF-CM and human LIF protein significantly promoted stemness through the dedifferentiation process and regaining of stem-cell-like properties. In addition, the results indicate that activation of LIFR signaling in breast cancer cells in the existence of CAF-secreted LIF can induce Nanog and Oct4 expression and increase breast cancer stem cell markers CD24−/CD44+. In contrast, suppression of the LIF receptor by human LIF receptor inhibition antibody decreased the cancer stem cell markers. We found that LIF was frequently overexpressed by CAFs and that LIF expression is necessary for dedifferentiation of breast cancer cell phenotype and regaining of cancer stem cell properties. Our results suggest that targeting LIF/LIFR signaling might be a potent therapeutic strategy for breast cancer and the prevention of tumor recurrence.

Relationship between CD 163 Tumor-Associated Macrophages and Colorectal-Cancer Stem Cell Markers

BACKGROUND: Colorectal-cancer stem cells (CR-CSCs) represent a specific subpopulation of colorectal cancer (CRC) cells, which are characterized by the expression of CD133 and CD166. Tumor-associated macrophages (TAMs), found near CSCs may represent polarized macrophages, which are characterized by CD163 expression. In most tumors, TAMs may promote aggressive tumor development, leading to poor prognoses. AIM: The aim of this study was to determine whether any association exists between CD163 expression in TAMs and CD133 and CD166 expression in CR-CSCs. METHODS: This study used a cross-sectional design that was conducted at the General Hospital and affiliates in Medan, from September 2018 to July 2019. CRC tissues were collected from colonoscopy biopsies and surgical resections performed on CRC patients, who fulfilled all necessary inclusion and exclusion criteria and provided informed consent. Subjects were divided into high- and low-CD163-level groups. We analyzed the expression levels of CD163, CD133, and CD166 using immunohistochemical (IHC) assays. RESULTS: A total of 118 CRC patients were enrolled in this study, of whom 58.5% were male. No significant differences in hemoglobin, leukocyte, or platelet levels were observed between high- and low-level CD163 expression. We didn’t find any significant association of CD163 TAM with CRC histological grade and TNM stagings. Significant associations were found between the CD 163 expression level and the CD133 expression level (p < 0.001) and between the CD 163 expression level and the CD166 expression level (p< 0.001). Increased TAM levels of CD163 was associated with 2.770-fold and 2.616-fold increased risks of elevated CD133 and CD166 levels, respectively. CONCLUSION: An association was found between the expression levels of CD163 in TAMs and the expression levels of CD133 and CD166 in CR-CSCs.