ALDH1A1 as a marker for metastasis initiating cells: A mechanistic insight.

Since metastasis accounts for the majority of cancer morbidity and mortality, attempts are focused to block metastasis and metastasis initiating cellular programs. It is generally believed that hypoxia, reactive oxygen species (ROS) and the dysregulated redox pathways regulate metastasis. Although induction of epithelial to mesenchymal transition (EMT) can initiate cell motility to different sites other than the primary site, the initiation of a secondary tumor at a distant site depends on self-renewal property of cancer stem cell (CSC) property.

Finding the partner: FRET and beyond.

Given the importance of aberrant protein-protein interactions (PPIs) in disease, the recent drug discovery focuses on targeting the altered PPIs to treat the disease. In this context, identifying the atypical PPIs underlying the disease is critical for the development of diagnostics and therapeutics. Various biochemical, biophysical, and genetic methods have been reported to study PPIs.

Elucidating the Role of MicroRNA-18a in Propelling a Hybrid Epithelial-Mesenchymal Phenotype and Driving Malignant Progression in ER-Negative Breast Cancer.

Epigenetic alterations that lead to differential expression of microRNAs (miRNAs/miR) are known to regulate tumour cell states, epithelial-mesenchymal transition (EMT) and the progression to metastasis in breast cancer. This study explores the key contribution of miRNA-18a in mediating a hybrid E/M cell state that is pivotal to the malignant transformation and tumour progression in the aggressive ER-negative subtype of breast cancer. The expression status and associated effects of miR-18a were evaluated in patient-derived breast tumour samples in combination with gene expression data from public datasets, and further validated in in vitro and in vivo breast cancer model systems.

HES1 promoter activation dynamics reveal the plasticity, stemness and heterogeneity in neuroblastoma cancer stem cells.

Notch signaling and its downstream gene target HES1 play a critical role in regulating and maintaining cancer stem cells (CSCs), similar to as they do during embryonic development. Here, we report a unique subclass of Notch-independent Hes-1 (NIHes-1)-expressing CSCs in neuroblastoma. These CSCs maintain sustained HES1 expression by activation of HES1 promoter region upstream of classical CBF-1 binding sites, thereby completely bypassing Notch receptor-mediated activation.

Tubulin Isotypes: Emerging Roles in Defining Cancer Stem Cell Niche.

Although the role of microtubule dynamics in cancer progression is well-established, the roles of tubulin isotypes, their cargos and their specific function in the induction and sustenance of cancer stem cells (CSCs) were poorly explored. But emerging reports urge to focus on the transport function of tubulin isotypes in defining orchestrated expression of functionally critical molecules in establishing a stem cell niche, which is the key for CSC regulation. In this review, we summarize the role of specific tubulin isotypes in the transport of functional molecules that regulate metabolic reprogramming, which leads to the induction of CSCs and immune evasion.

β-Tubulin Isotype, TUBB4B, Regulates The Maintenance of Cancer Stem Cells.

Recent advancements in cancer research have shown that cancer stem cell (CSC) niche is a crucial factor modulating tumor progression and treatment outcomes. It sustains CSCs by orchestrated regulation of several cytokines, growth factors, and signaling pathways. Although the features defining adult stem cell niches are well-explored, the CSC niche is poorly characterized.

Histone Chaperone Nucleophosmin Regulates Transcription of Key Genes Involved in Oral Tumorigenesis.

Nucleophosmin (NPM1) is a multifunctional histone chaperone that can activate acetylation-dependent transcription from chromatin templates . p300-mediated acetylation of NPM1 has been shown to further enhance its transcription activation potential. Acetylated and total NPM1 pools are increased in oral squamous cell carcinoma.

SSTP1, a Host Defense Peptide, Exploits the Immunomodulatory IL6 Pathway to Induce Apoptosis in Cancer Cells.

While the immunomodulatory pathways initiated in immune cells contribute to therapeutic response, their activation in cancer cells play a role in cancer progression. Also, many of the aberrantly expressed immunomodulators on cancer cells are considered as therapeutic targets. Here, we introduce host defense peptide (HDP), a known immuomodulator, as a therapeutic agent to target them.

Markers and Reporters to Reveal the Hierarchy in Heterogeneous Cancer Stem Cells.

A subpopulation within cancer, known as cancer stem cells (CSCs), regulates tumor initiation, chemoresistance, and metastasis. At a closer look, CSCs show functional heterogeneity and hierarchical organization. The present review is an attempt to assign marker profiles to define the functional heterogeneity and hierarchical organization of CSCs, based on a series of single-cell analyses.

Reporters of Cancer Stem Cells as a Tool for Drug Discovery.

In view of the importance of cancer stem cells (CSCs) in chemoresistance, metastasis and recurrence, the biology of CSCs were explored in detail. Based on that, several modalities were proposed to target them. In spite of the several clinical trials, a successful CSC-targeting drug is yet to be identified.

B1CTcu5: A frog-derived brevinin-1 peptide with anti-tuberculosis activity.

Tuberculosis (TB) is a devastating infectious disease that causes a high rate of mortality. Drugs with new modes of action are needed to overcome this scenario. Cationic antibacterial peptides can serve as a potential alternative to existing TB drugs as they target the entire bacterial membrane for activity, thereby reducing the probability of development of drug resistance.

A novel reporter construct for screening small molecule inhibitors that specifically target self-renewing cancer cells.

Cancer stem cells (CSCs) are a subset of cancer cells, which possess self-renewal ability, and lead to tumor progression, metastasis, and resistance to therapy. Live detection and isolation of CSCs are important to understand the biology of CSCs as well as to screen drugs that target them. Even though CSCs are detected using surface markers, there is a lot of inconsistencies for that in a given cancer type.

TM1-IR680 peptide for assessment of surgical margin and lymph node metastasis in murine orthotopic model of oral cancer.

Treatment outcome after surgical removal in oral carcinoma is poor due to inadequate methodologies available for marking surgical margins. Even though some methodologies for intraoperative margin assessment are under clinical and preclinical trials for other solid tumours, a promising modality for oral cancer surgery is not developed. Fluorescent-based optical imaging using Near Infrared (NIR) dyes tagged to tumour specific target will be an optimal tool for this purpose.

Single cell biology beyond the era of antibodies: relevance, challenges, and promises in biomedical research.

Research of the past two decades has proved the relevance of single cell biology in basic research and translational medicine. Successful detection and isolation of specific subsets is the key to understand their functional heterogeneity. Antibodies are conventionally used for this purpose, but their relevance in certain contexts is limited.

Live detection and purification of cells based on the expression of a histone chaperone, HIRA, using a binding peptide.

Flow cytometry is a reliable method for identification and purification of live cells from a heterogeneous population. Since permeabilized cells cannot be sorted live in a FACS sorter, its application in isolation of functional cells largely depends on antibodies for surface markers. In various fields of biology we find intracellular markers that reveal subpopulations of biological significance.

Phytochemicals as chemosensitizers: from molecular mechanism to clinical significance.

This review provides an overview of the clinical relevance of chemosensitization, giving special reference to the phenolic phytochemicals, curcumin, genistein, epigallocatechin gallate, quercetin, emodin, and resveratrol, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity. We also give a brief summary of all the clinical trials related to the important phytochemicals that emerge as chemosensitizers. The mode of action of these phytochemicals in regulating the key players of the death receptor pathway and multidrug resistance proteins is also abridged.

Notch signaling in CD66+ cells drives the progression of human cervical cancers.

Human epithelial tumor progression and metastasis involve cellular invasion, dissemination in the vasculature, and regrowth at metastatic sites. Notch signaling has been implicated in metastatic progression but its roles have yet to be fully understood. Here we report the important role of Notch signaling in maintaining cells expressing the carcinoembryonic antigen cell adhesion molecule CEACAM (CD66), a known mediator of metastasis.

Cell intrinsic & extrinsic factors in cervical carcinogenesis.

Human papillomavirus (HPV) infection is a common sexually transmitted infection which a majority of infected women are able to clear by mounting an effective immune response. Individuals with a suboptimal immune response may be at increased risk of persistent HPV infection leading to sequelae of various grades of dysplasias and / or associated malignancy. Both cell intrinsic and extrinsic phenomena work in concert to bring about oncogenesis.

Coexpression of Notch1 and NF-kappaB signaling pathway components in human cervical cancer progression.

Objectives: Features of deregulated Notch1 signaling and NF-kappaB activation have independently been reported in cervical cancers. Here, we have extended these observations and examined both these pathways simultaneously in human cervical cancer tissue. Further, we have investigated the potential cross-talk between these pathways in a human cervical cancer derived cell line CaSki, which mirrors features of Notch activation as in the majority of human cervical cancers.

Differential activation of Smads in HeLa and SiHa cells that differ in their response to transforming growth factor-beta.

We assessed the responsiveness of six human cervical cancer cell lines to transforming growth factor (TGF)-beta with p3TP-lux reporter assay and found that HeLa and SiHa cells were highly responsive to TGF-beta. However, when pSBE4-BV/Luc reporter with four Smad binding elements was used, only the SiHa, not the HeLa, cells showed Smad activation. Smad DNA binding activity was relatively more in SiHa than in HeLa cells upon TGF-beta treatment, and the active complex contained Smad 2 and Smad 4.

Loss of expression, and mutations of Smad 2 and Smad 4 in human cervical cancer.

Mutations in Smads, intermediates of transforming growth factor-beta signaling, are known to contribute to the loss of sensitivity to transforming growth factor-beta, a common feature of many neoplastic cells. However, not much information is available on Smad alterations in cervical cancer and so we probed, for the first time, for alterations in Smad 2 and Smad 4 genes using human cervical cancer cell lines and human cervical tissue samples. Using PCR/reverse transcription-PCR, single-stranded conformation polymorphism analysis and DNA sequencing, we observed a deletion of 'G' in the L3 loop (crucial in Smad-receptor interaction) in C-33A cells, and an insertion of 'A' in codon 122 (loss of MH2 domain) from a cervical tumor sample, both of which caused frame shift and pretermination in Smad 2.

NF-kappaB is constitutively activated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix.

We demonstrate, for the first time, that the transcription factor NF-kappaB is constitutively activated during human cervical cancer progression. Immunohistochemical analysis was done using 106 paraffin-embedded cervical tissue specimens of different histological grades. In normal cervical tissue and low-grade squamous intraepithelial lesions, p50, RelA and IkappaB-alpha were mainly localized in the cytosol, whereas in high-grade lesions and squamous cell carcinomas, p50-RelA heterodimers translocated into the nucleus with a concurrent decrease in IkappaB-alpha protein.