Reporters of Cancer Stem Cells as a Tool for Drug Discovery

Mohan, Amrutha; R, Reshma Raj; Mohan, Gayathri; Padmaja, K P; Maliekal, Tessy Thomas

doi:10.3389/fonc.2021.669250

Cited by 24 publications

(15 citation statements)

References 162 publications

(139 reference statements)

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“…We also detected higher CD44 levels. Circulating double positive CD44 and ALDH1/2 cells were shown to have an increased capacity for tumor initiation and are characteristic for cancer stem-like cells [ 34 ]. As found in the risk prediction analysis of our identified 67-gene signature, overexpressed Neuropilin (NRP2) and LAMC1 also appeared as determinants of worse prognosis.…”

Section: Discussionmentioning

confidence: 99%

A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer

Bueno-Fortes

Muenzner

Berral-González

et al. 2021

Cancers

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The epithelial–mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.

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Section: Discussionmentioning

confidence: 99%

A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer

Bueno-Fortes

Muenzner

Berral-González

et al. 2021

Cancers

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“…Several transcription factors such as Nanog, SOX2, and Oct4 maintain the characteristics of CSCs; hence, they are often used as markers for CSCs [29,30]. BCSCs share similarities with healthy adult stem cells, including their sphere-forming ability and self-renewability.…”

Section: Discussionmentioning

confidence: 99%

Small peptide LINC00511-133aa encoded by LINC00511 regulates breast cancer cell invasion and stemness through the Wnt/β-catenin pathway

Tan

Zhao

Huang

et al. 2022

Preprint

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The stemness and invasion of breast cancer cells are key causative factors for tumor relapse and metastasis. The present study aimed to identify whether LINC00511-133aa, a small peptide encoded by LINC00511, could mediate the wnt/β-catenin pathway to control the invasiveness and stemness of breast cancer cells. In this study, LINC00511-133aa and control vector were transfected into breast cancer cells (MCF-7 and MDA-MB-231). Afterward,) PCR, western blot, and immunofluorescence assays were conducted to assess the expression of the small peptide LINC00511-133aa. Cell proliferative and invasive potentials were subsequently evaluated using CCK8, apoptotic, scratch, and transwell invasion assays. Finally, cancer stem cell-like characteristics were identified by the sphere-forming assay and western blot analysis of the stemness markers (Oct4, Nanog, and SOX2). The results show that the small peptide LINC00511-133aa was determined to be encoded by LINC00511. Transfection with this peptide expedited the invasion ability of breast cancer cells, strengthened their stemness, and limited apoptosis. Finally, LINC00511-133aa activated the wnt/β-catenin pathway. in sum, LINC00511 can encode the small peptide LINC00511-133aa, which can modulate the invasiveness and stemness through the regulation of the wnt/β-catenin pathway.

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“…Epigenetic modification of OCT4 is a common event in the evolution of cancers. Tryptophan-induced OCT4 transcription inhibitor 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) can significantly suppress tumor formation and tumor growth in the mouse subcutaneous tumor model and in vivo ectopic implantation model (118)(119)(120).…”

Section: The Role Of Cancer Evo-dev On Identification Of New Therapeutic Targets For Cancersmentioning

confidence: 99%

Cancer Evo–Dev: A Theory of Inflammation-Induced Oncogenesis

Liu

Deng

et al. 2021

Front. Immunol.

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Chronic inflammation is a prerequisite for the development of cancers. Here, we present the framework of a novel theory termed as Cancer Evolution-Development (Cancer Evo-Dev) based on the current understanding of inflammation-related carcinogenesis, especially hepatocarcinogenesis induced by chronic infection with hepatitis B virus. The interaction between genetic predispositions and environmental exposures, such as viral infection, maintains chronic non-resolving inflammation. Pollution, metabolic syndrome, physical inactivity, ageing, and adverse psychosocial exposure also increase the risk of cancer via inducing chronic low-grade smoldering inflammation. Under the microenvironment of non-resolving inflammation, pro-inflammatory factors facilitate the generation of somatic mutations and viral mutations by inducing the imbalance between the mutagenic forces such as cytidine deaminases and mutation-correcting forces including uracil–DNA glycosylase. Most cells with somatic mutations and mutated viruses are eliminated in survival competition. Only a small percentage of mutated cells survive, adapt to the hostile environment, retro-differentiate, and function as cancer-initiating cells via altering signaling pathways. These cancer-initiating cells acquire stem-ness, reprogram metabolic patterns, and affect the microenvironment. The carcinogenic process follows the law of “mutation-selection-adaptation”. Chronic physical activity reduces the levels of inflammation via upregulating the activity and numbers of NK cells and lymphocytes and lengthening leukocyte telomere; downregulating proinflammatory cytokines including interleukin-6 and senescent lymphocytes especially in aged population. Anti-inflammation medication reduces the occurrence and recurrence of cancers. Targeting cancer stemness signaling pathways might lead to cancer eradication. Cancer Evo-Dev not only helps understand the mechanisms by which inflammation promotes the development of cancers, but also lays the foundation for effective prophylaxis and targeted therapy of various cancers.

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Reporters of Cancer Stem Cells as a Tool for Drug Discovery

Cited by 24 publications

References 162 publications

A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer

A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer

Small peptide LINC00511-133aa encoded by LINC00511 regulates breast cancer cell invasion and stemness through the Wnt/β-catenin pathway

Cancer Evo–Dev: A Theory of Inflammation-Induced Oncogenesis

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