Cancer Stem Cell Niche in Colorectal Cancer and Targeted Therapies

2020 ◽  
Vol 26 (17) ◽  
pp. 1979-1993 ◽  
Author(s):  
Hao Wang ◽  
Guihua Cui ◽  
Bo Yu ◽  
Meiyan Sun ◽  
Hong Yang
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell Niche ◽  
Tumor Initiating Cells ◽  
Ideal Model ◽  
Cytotoxic Effects ◽  
Therapeutic Value ◽  
Cancer Initiation ◽  
Cell Niche ◽  
New Strategies ◽  
Common Malignancy

Cancer stem cells (CSCs), also known as tumor-initiating cells, are a sub-population of tumor cells found in many human cancers that are endowed with self-renewal and pluripotency. CSCs may be more resistant to conventional anticancer therapies than average cancer cells, as they can easily escape the cytotoxic effects of standard chemotherapy, thereby resulting in tumor relapse. Despite significant progress in related research, effective elimination of CSCs remains an unmet clinical need. CSCs are localized in a specialized microenvironment termed the niche, which plays a pivotal role in cancer multidrug resistance. The niche components of CSCs, such as the extracellular matrix, also physically shelter CSCs from therapeutic agents. Colorectal cancer is the most common malignancy worldwide and presents a relatively transparent process of cancer initiation and development, making it an ideal model for CSC niche research. Here, we review recent advances in the field of CSCs using colorectal cancer as an example to illustrate the potential therapeutic value of targeting the CSC niche. These findings not only provide a novel theoretical basis for in-depth discussions on tumor occurrence, development, and prognosis evaluation, but also offer new strategies for the targeted treatment of cancer.

scholarly journals Immunostaining of Lgr5, an Intestinal Stem Cell Marker, in Normal and Premalignant Human Gastrointestinal Tissue

2008 ◽  
Vol 8 ◽  
pp. 1168-1176 ◽  
Author(s):  
Laren Becker ◽  
Qin Huang ◽  
Hiroshi Mashimo
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Intestinal Stem Cells ◽  
Stem Cell Marker ◽  
Tumor Initiating Cells ◽  
Colonic Adenomas ◽  
Potential Marker ◽  
Cell Niche ◽  
Crypt Base

Lgr5 has recently been identified as a murine marker of intestinal stem cells. Its expression has not been well characterized in human gastrointestinal tissues, but has been reported in certain cancers. With the increasing appreciation for the role of cancer stem cells or tumor-initiating cells in certain tumors, we sought to explore the expression of Lgr5 in normal and premalignant human gastrointestinal tissues. Using standard immunostaining, we compared expression of Lgr5 in normal colon and small intestine vs. small intestinal and colonic adenomas and Barrett's esophagus. In the normal tissue, Lgr5 was expressed in the expected stem cell niche, at the base of crypts, as seen in mice. However, in premalignant lesions, Lgr5+cells were not restricted to the crypt base. Additionally, their overall numbers were increased. In colonic adenomas, Lgr5+cells were commonly found clustered at the luminal surface and rarely at the crypt base. Finally, we compared immunostaining of Lgr5 with that of CD133, a previously characterized marker for tumor-initiating cells in colon cancer, and found that they identified distinct subpopulations of cells that were in close proximity, but did not costain. Our findings suggest that (1) Lgr5 is a potential marker of intestinal stem cells in humans and (2) loss of restriction to the stem cell niche is an early event in the premalignant transformation of stem cells and may play a role in carcinogenesis.

scholarly journals Collagen IV differentially regulates planarian stem cell potency and lineage progression

2021 ◽  
Vol 118 (16) ◽  
pp. e2021251118
Author(s):  
Andy Chan ◽  
Sophia Ma ◽  
Bret J. Pearson ◽  
Danny Chan
Keyword(s):  
Stem Cell ◽  
Stem Cell Niche ◽  
Type Iv Collagen ◽  
Large Population ◽  
Ideal Model ◽  
Multipotent Stem Cells ◽  
Stem Cell Regulation ◽  
Type Iv ◽  
Cell Niche

The extracellular matrix (ECM) provides a precise physical and molecular environment for cell maintenance, self-renewal, and differentiation in the stem cell niche. However, the nature and organization of the ECM niche is not well understood. The adult freshwater planarian Schmidtea mediterranea maintains a large population of multipotent stem cells (neoblasts), presenting an ideal model to study the role of the ECM niche in stem cell regulation. Here we tested the function of 165 planarian homologs of ECM and ECM-related genes in neoblast regulation. We identified the collagen gene family as one with differential effects in promoting or suppressing proliferation of neoblasts. col4-1, encoding a type IV collagen α-chain, had the strongest effect. RNA interference (RNAi) of col4-1 impaired tissue maintenance and regeneration, causing tissue regression. Finally, we provide evidence for an interaction between type IV collagen, the discoidin domain receptor, and neuregulin-7 (NRG-7), which constitutes a mechanism to regulate the balance of symmetric and asymmetric division of neoblasts via the NRG-7/EGFR pathway.

scholarly journals Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

2021 ◽  
Vol 22 (7) ◽  
pp. 3606
Author(s):  
Deniz Caylioglu ◽  
Rieke Johanna Meyer ◽  
Dana Hellmold ◽  
Carolin Kubelt ◽  
Michael Synowitz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Niche ◽  
Treatment Strategies ◽  
Inhibitory Influence ◽  
Glioma Stem Cell ◽  
Cytotoxic Effects ◽  
Interleukin 6 Receptor ◽  
Cell Subpopulations ◽  
Cell Niche ◽  
Higher Sensitivity

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.

scholarly journals Alternative splicing of mRNA in colorectal cancer: new strategies for tumor diagnosis and treatment

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Yanyan Chen ◽  
Mengxi Huang ◽  
Xiaolong Liu ◽  
Yadi Huang ◽  
Chao Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Alternative Splicing ◽  
Therapeutic Strategy ◽  
The Past ◽  
Mature Transcript ◽  
Posttranscriptional Gene Regulation ◽  
Therapeutic Value ◽  
Multistep Process ◽  
Effective Therapeutic Strategy ◽  
New Strategies

AbstractAlternative splicing (AS) is an important event that contributes to posttranscriptional gene regulation. This process leads to several mature transcript variants with diverse physiological functions. Indeed, disruption of various aspects of this multistep process, such as cis- or trans- factor alteration, promotes the progression of colorectal cancer. Therefore, targeting some specific processes of AS may be an effective therapeutic strategy for treating cancer. Here, we provide an overview of the AS events related to colorectal cancer based on research done in the past 5 years. We focus on the mechanisms and functions of variant products of AS that are relevant to malignant hallmarks, with an emphasis on variants with clinical significance. In addition, novel strategies for exploiting the therapeutic value of AS events are discussed.

scholarly journals Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways

2020 ◽  
Vol 40 (3) ◽  
Author(s):  
Mao-lin Wan ◽  
Yu Wang ◽  
Zhi Zeng ◽  
Bo Deng ◽  
Bi-sheng Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Unique Feature ◽  
Biological Function ◽  
Molecular Signaling ◽  
Biological Functions ◽  
The Third ◽  
Multiple Signaling ◽  
New Strategies ◽  
Common Malignancy

Abstract Colorectal cancer (CRC) is the third most common malignancy and one of the leading causes of cancer-related death among men worldwide. CRC is a multifactor digestive pathology, which is a huge problem faced not only by clinicians but also by researchers. Importantly, a unique feature of CRC is the dysregulation of molecular signaling pathways. To date, a series of reviews have indicated that different signaling pathways are disordered and have potential as therapeutic targets in CRC. Nevertheless, an overview of the function and interaction of multiple signaling pathways in CRC is needed. Therefore, we summarized the pathways, biological functions and important interactions involved in CRC. First, we investigated the involvement of signaling pathways, including Wnt, PI3K/Akt, Hedgehog, ErbB, RHOA, Notch, BMP, Hippo, AMPK, NF-κB, MAPK and JNK. Subsequently, we discussed the biological function of these pathways in pathophysiological aspects of CRC, such as proliferation, apoptosis and metastasis. Finally, we summarized important interactions among these pathways in CRC. We believe that the interaction of these pathways could provide new strategies for the treatment of CRC.

scholarly journals The role of melatonin in colorectal cancer treatment: a comprehensive review

2020 ◽  
Vol 12 ◽  
pp. 175883592093171
Author(s):  
Mindaugas Kvietkauskas ◽  
Viktorija Zitkute ◽  
Bettina Leber ◽  
Kestutis Strupas ◽  
Philipp Stiegler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Multimodal Treatment ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Cytotoxic Effects ◽  
Comprehensive Review ◽  
Stage Disease ◽  
Different Types ◽  
New Strategies

Colorectal cancer (CRC) is one of the most common types of cancer worldwide, known as the second leading cause of cancer-related deaths annually. Currently, multimodal treatment strategies, including surgical resection, combined with chemotherapy and radiotherapy, have been used as conventional treatments in patients with CRC. However, clinical outcome of advanced stage disease remains relatively discouraging, due mainly to appearance of CRC chemoresistance, toxicity, and other detrimental side effects. New strategies to overcome these limitations are essential. During the last decades, melatonin (MLT) has been shown to be a potent antiproliferative, anti-metastatic agent with cytotoxic effects on different types of human malignancies, including CRC. Hence, this comprehensive review compiles the available experimental and clinical data analyzing the effects of MLT treatment in CRC patients and its underlying molecular mechanisms.

scholarly journals S1P Lyase Regulates Intestinal Stem Cell Quiescence via Ki-67 and FOXO3

2021 ◽  
Vol 22 (11) ◽  
pp. 5682
Author(s):  
Anja Schwiebs ◽  
Farha Faqar-Uz-Zaman ◽  
Martina Herrero San Juan ◽  
Heinfried H. Radeke
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Stem Cell ◽  
Signaling Pathway ◽  
Stem Cell Niche ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Ki 67 ◽  
Cell Niche ◽  
S1p Lyase

Background: Reduction of the Sphingosine-1-phosphate (S1P) degrading enzyme S1P lyase 1 (SGPL1) initiates colorectal cancer progression with parallel loss of colon function in mice. We aimed to investigate the effect of SGPL1 knockout on the stem cell niche in these mice. Methods: We performed immunohistochemical and multi-fluorescence imaging on tissue sections of wildtype and SGPL1 knockout colons under disease conditions. Furthermore, we generated SGPL1 knockout DLD-1 cells (SGPL1−/−M.Ex1) using CRISPR/Cas9 and characterized cell cycle and AKT signaling pathway via Western blot, immunofluorescence, and FACS analysis. Results: SGPL1 knockout mice were absent of anti-Ki-67 staining in the stem cell niche under disease conditions. This was accompanied by an increase of the negative cell cycle regulator FOXO3 and attenuation of CDK2 activity. SGPL1−/−M.Ex1 cells show a similar FOXO3 increase but no arrest of proliferation, although we found a suppression of the PDK1/AKT signaling pathway, a prolonged G1-phase, and reduced stem cell markers. Conclusions: While already established colon cancer cells find escape mechanisms from cell cycle arrest, in vivo SGPL1 knockout in the colon stem cell niche during progression of colorectal cancer can contribute to cell cycle quiescence. Thus, we propose a new function of the S1P lyase 1 in stemness.

Tissue Stem Cells and Stem Cell Niche of the Human Vocal Fold

2020 ◽  
Vol 71 (2) ◽  
pp. 211-213
Author(s):  
K. Sato ◽  
S. Chitose ◽  
K. Sato ◽  
F. Sato ◽  
T. Kurita ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Vocal Fold ◽  
Cell Niche
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