Cell Reversal From a Differentiated to a Stem-Like State at Cancer Initiation

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.

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Molecular Processes Involved in Pancreatic Cancer and Therapeutics

Current Chemical Biology ◽

10.2174/2212796814999201008130819 ◽

2020 ◽

Vol 14 ◽

Author(s):

Subhajit Makar ◽

Abhrajyoti Ghosh ◽

Divya ◽

Shalini Shivhare ◽

Ashok Kumar ◽

...

Keyword(s):

Pancreatic Cancer ◽

Molecular Mechanisms ◽

Early Stage ◽

Locally Advanced ◽

Therapeutic Strategies ◽

Screening Methods ◽

Pancreatic Cancer Cells ◽

Systemic Treatments ◽

Cancer Initiation ◽

Novel Therapeutic Strategies

: Despite advances in the development of cytotoxic and targeted therapies, pancreatic adenocarcinoma (PAC) remains a significant cause of cancer mortality worldwide. It is also difficult to detect it at an early stage due to numbers of factors. Most of the patients are present with locally advanced or metastatic disease, which precludes curative resection. In the absence of effective screening methods, considerable efforts have been made to identify better systemic treatments during the past decade. This review describes the recent advances in molecular mechanisms involved in pancreatic cancer initiation, progression, and metastasis. Additionally, the importance of deregulated cellular signalling pathways and various cellular proteins as potential targets for developing novel therapeutic strategies against incurable forms of pancreatic cancer is reported. The emphasis is on the critical functions associated with growth factors and their receptors viz. c-MET/HGF, CTHRC1, TGF-β, JAK-STAT, cyclooxygenase pathway, WNT, CCK, MAPK-RAS-RAF, PI3K-AKT, Notch, src, IGF-1R, CDK2NA and chromatin regulation for the sustained growth, survival, and metastasis of pancreatic cancer cells. It also includes various therapeutic strategies viz. immunotherapy, surgical therapy, radiation therapy and chemotherapy.

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Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma

International Journal of Molecular Sciences ◽

10.3390/ijms22052602 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2602

Author(s):

Emilie Viennois ◽

Benoit Chassaing

Keyword(s):

Intestinal Inflammation ◽

Tumor Development ◽

Low Grade ◽

Gastrointestinal Cancers ◽

Cancer Initiation ◽

And Function ◽

The Impact ◽

Chronic Intestinal Inflammation ◽

Low Grade Inflammation ◽

Intestinal Adenoma

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers’ impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host–microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.

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A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer

Cancers ◽

10.3390/cancers13122873 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2873

Author(s):

Shu-Chun Chang ◽

Chin-Sheng Hung ◽

Bo-Xiang Zhang ◽

Tsung-Han Hsieh ◽

Wayne Hsu ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cell ◽

Mrna Level ◽

Breast Carcinogenesis ◽

E3 Ligases ◽

Anti Cancer ◽

Cancer Initiation ◽

Cell Progression ◽

F Box Protein ◽

Cancer Activity

Breast cancer (BRCA) malignancy causes major fatalities amongst women worldwide. SCF (Skp1-cullin-F-box proteins) E3 ubiquitin ligases are the most well-known members of the ubiquitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCFF-boxes) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCFF-boxes is a key component of E3 ligases, we hypothesized that other SCFF-boxes besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregulation of four SCFF-box E3 ligases (FBXL8, FBXO43, FBXO15, and CCNF) in the carcinoma tissues. Similar to FBXL8, the knockdown of FBXO43 reduced cancer cell viability and proliferation, suggesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. Unexpectedly, CCNF protein was markedly downregulated in BRCA tissues, although its mRNA level was high. We showed that both E3 ligases, FBXL8 and FZR1, pulled down CCNF. Double knockdown of FBXL8 and FZR1 caused CCNF accumulation. On the other hand, CCNF itself pulled down a tumorigenic factor, RRM2, and CCNF overexpression reduced RRM2. Altogether, we propose a signature network of E3 ligases that collaboratively modulates CCNF anti-cancer activity. There is potential to target BRCA through modulation of the partnership axes of (i) CCNF-FBXL8, (ii) CCNF-FZR1, and (iii) CCNF-RRM2, particularly, via CCNF overexpression and activation and FBXL8/FZR1 suppression.

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