scholarly journals Patient derived organoids reveal that PI3K/AKT signaling is an escape pathway for radioresistance and a target for therapy in rectal cancer.

2021 ◽  
Author(s):  
Kasun Wanigasooriya ◽  
Joao D Barros-Silva ◽  
Louise Tee ◽  
Mohammed E Elasrag ◽  
Agata Stodolna ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Locally Advanced ◽  
Mtor Inhibitors ◽  
Mesenchymal Transition ◽  
Post Irradiation ◽  
A Genome ◽  
Resistance Pathway ◽  
Radiation Resistant

Partial or total resistance to preoperative chemoradiotherapy occurs in more than half of locally advanced rectal cancer patients. Several novel or repurposed drugs have been trialled to improve cancer cell sensitivity to radiotherapy, with limited success. To understand the mechanisms underlying this resistance and target them effectively, we initially compared treatment-naive transcriptomes of radiation-resistant and radiation-sensitive patient-derived organoids (PDO) to identify biological pathways involved in radiation resistance. Pathway analysis revealed that PI3K/AKT/mTOR and epithelial mesenchymal transition pathway genes were upregulated in radioresistant PDOs. Moreover, single-cell sequencing of pre & post-irradiation PDOs showed mTORC1 upregulation, which was confirmed by a genome-wide CRSIPR-Cas9 knockout screen using irradiated colorectal cancer (CRC) cell lines. Based on these findings, we evaluated cancer cell viability in vitro when treated with radiation in combination with dual PI3K/mTOR inhibitors apitolisib or dactolisib. Significant AKT phosphorylation was detected in HCT116 cells two hours post-irradiation (p=0.027). Dual PI3K/mTOR inhibitors radiosensitised HCT116 and radiation-resistant PDO lines. The PI3K/AKT/mTOR pathway upregulation contributes to radioresistance and its pharmacological inhibition leads to significant radiosensitisation in an organoid model of CRC and is a target for clinical trials.

scholarly journals Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1102
Author(s):  
Alexander E. Kabakov ◽  
Anna O. Yakimova
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Liver Tumors ◽  
Oxygen Deficiency ◽  
Transarterial Embolization ◽  
Antiangiogenic Therapy ◽  
Adaptation To Hypoxia ◽  
Mesenchymal Transition

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.

scholarly journals Co-Overexpression of TWIST1-CSF1 Is a Common Event in Metastatic Oral Cancer and Drives Biologically Aggressive Phenotype

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 153
Author(s):  
Sabrina Daniela da Silva ◽  
Fabio Albuquerque Marchi ◽  
Jie Su ◽  
Long Yang ◽  
Ludmila Valverde ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Inflammatory Cells ◽  
Rank Test ◽  
Mesenchymal Transition ◽  
Genome Wide ◽  
A Genome ◽  
Enhanced Expression ◽  
Advanced Stages

Invasive oral squamous cell carcinoma (OSCC) is often ulcerated and heavily infiltrated by pro-inflammatory cells. We conducted a genome-wide profiling of tissues from OSCC patients (early versus advanced stages) with 10 years follow-up. Co-amplification and co-overexpression of TWIST1, a transcriptional activator of epithelial-mesenchymal-transition (EMT), and colony-stimulating factor-1 (CSF1), a major chemotactic agent for tumor-associated macrophages (TAMs), were observed in metastatic OSCC cases. The overexpression of these markers strongly predicted poor patient survival (log-rank test, p = 0.0035 and p = 0.0219). Protein analysis confirmed the enhanced expression of TWIST1 and CSF1 in metastatic tissues. In preclinical models using OSCC cell lines, macrophages, and an in vivo matrigel plug assay, we demonstrated that TWIST1 gene overexpression induces the activation of CSF1 while TWIST1 gene silencing down-regulates CSF1 preventing OSCC invasion. Furthermore, excessive macrophage activation and polarization was observed in co-culture system involving OSCC cells overexpressing TWIST1. In summary, this study provides insight into the cooperation between TWIST1 transcription factor and CSF1 to promote OSCC invasiveness and opens up the potential therapeutic utility of currently developed antibodies and small molecules targeting cancer-associated macrophages.

scholarly journals MiR-205 Dysregulations in Breast Cancer: The Complexity and Opportunities

2019 ◽  
Vol 5 (4) ◽  
pp. 53 ◽  
Author(s):  
Xiao ◽  
Humphries ◽  
Yang ◽  
Wang
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Target Gene ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Therapy Resistance ◽  
Cancer Cell Proliferation ◽  
Mesenchymal Transition

MicroRNAs (miRNAs) are endogenous non-coding small RNAs that downregulate target gene expression by imperfect base-pairing with the 3′ untranslated regions (3′UTRs) of target gene mRNAs. MiRNAs play important roles in regulating cancer cell proliferation, stemness maintenance, tumorigenesis, cancer metastasis, and cancer therapeutic resistance. While studies have shown that dysregulation of miRNA-205-5p (miR-205) expression is controversial in different types of human cancers, it is generally observed that miR-205-5p expression level is downregulated in breast cancer and that miR-205-5p exhibits a tumor suppressive function in breast cancer. This review focuses on the role of miR-205-5p dysregulation in different subtypes of breast cancer, with discussions on the effects of miR-205-5p on breast cancer cell proliferation, epithelial–mesenchymal transition (EMT), metastasis, stemness and therapy-resistance, as well as genetic and epigenetic mechanisms that regulate miR-205-5p expression in breast cancer. In addition, the potential diagnostic and therapeutic value of miR-205-5p in breast cancer is also discussed. A comprehensive list of validated miR-205-5p direct targets is presented. It is concluded that miR-205-5p is an important tumor suppressive miRNA capable of inhibiting the growth and metastasis of human breast cancer, especially triple negative breast cancer. MiR-205-5p might be both a potential diagnostic biomarker and a therapeutic target for metastatic breast cancer.

scholarly journals Exo70 Isoform Switching upon Epithelial-Mesenchymal Transition Mediates Cancer Cell Invasion

2013 ◽  
Vol 27 (5) ◽  
pp. 560-573 ◽  
Author(s):  
Hezhe Lu ◽  
Jianglan Liu ◽  
Shujing Liu ◽  
Jingwen Zeng ◽  
Deqiang Ding ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cell Invasion ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Invasion ◽  
Mesenchymal Transition ◽  
Isoform Switching
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