development-of-drug-resistant-cell-lines-for-experimental-procedures

Development of Drug-resistant Cell Lines for Experimental Procedures

The development of drug-resistant cell lines is essential for understanding the mechanisms of drug resistance and identifying strategies to overcome ...

University of Michigan, Ann Arbor

PTH has anabolic and catabolic actions in bone that are not clearly understood. The protooncogene c-fos and other activating protein 1 family members are critical transcriptional mediators in bone, and c-fos is up-regulated by PTH. The purpose of this study was to examine the mechanisms of PTH and the role of c-fos in PTH-mediated anabolic actions in bone. Mice with ablation of c-fos (-/-) and their wild-type (+/+) and heterozygous (+/-) littermates were administered PTH for 17 d. The +/+ mice had increased femoral bone mineral density (BMD), whereas -/- mice had reduced BMD after PTH treatment. PTH increased the ash weight of +/+ and +/-, but not -/-, femurs and decreased the calcium content of -/-, but not +/+ or +/-, femurs. Histomorphometric analysis showed that PTH increased trabecular bone volume in c-fos +/+, +/- vertebrae, but, in contrast, decreased trabecular bone in -/- vertebrae. Serum calcium levels in +/+ mice were greater than those in -/- mice, and PTH increased calcium in -/- mice. Histologically, PTH resulted in an exacerbation of the already widened growth plate and zone of hypertrophic chondrocytes but not the proliferating zone in -/- mice. PTH also increased calvarial thickness in +/+ mice, but not -/- mice. The c-fos -/- mice had lower bone sialoprotein and osteocalcin (OCN), but unaltered PTH-1 receptor mRNA expression in calvaria, suggesting an alteration in extracellular matrix. Acute PTH injection (8 h) resulted in a decrease in osteocalcin mRNA expression in wild-type, but unaltered expression in -/-, calvaria. These data indicate that c-fos plays a critical role in the anabolic actions of PTH during endochondral bone growth.

Anabolic actions of parathyroid hormone during bone growth are dependent on c-fos.

There is an urgent need to apply basic research achievements to the clinic. In particular, mechanistic studies should be developed by bench researchers, depending upon clinical demands, in order to improve the survival and quality of life of cancer patients. To date, translational medicine has been addressed in cancer biology, particularly in the identification and characterization of novel tumor biomarkers. This review focuses on the recent achievements and clinical application prospects in tumor biomarkers based on translational medicine.

Translational progress on tumor biomarkers.

Despite advances in surgery, imaging, chemotherapy, and radiotherapy, the poor overall cancer-related death rate remains unacceptable. Novel therapeutic strategies are desperately needed. Nowadays, targeted therapy has become the most promising therapy and a welcome asset to the cancer therapeutic arena. There is a large body of evidence demonstrating that the Notch signaling pathway is critically involved in the pathobiology of a variety of malignancies. In this review, we provide an overview of emerging data, highlight the mechanism of the Notch signaling pathway in the development of a wide range of cancers, and summarize recent progress in therapeutic targeting of the Notch signaling pathway.

Targeting the Notch signaling pathway in cancer therapeutics.

Despite advanced efforts in early diagnosis, aggressive surgical treatment, and use of targeted chemotherapies, the prognosis for many cancers is still dismal. This emphasizes the necessity to develop new strategies for understanding tumor growth and metastasis. Here we use a systems approach that combines mathematical modeling and numerical simulation to develop a predictive computational model for prostate cancer and its subversion of the bone microenvironment. This model simulates metastatic prostate cancer evolution, progressing from normal bone and hormone levels to quantifiable diseased states. The simulations clearly demonstrate phenomena similar to those found clinically in prostate cancer patients. In addition, the major prediction of this model is the existence of low and high osteogenic states that are markedly different from one another. The existence and potential realization of these steady states appear to be mediated by the Wnt signaling pathway and by the effects of PSA on TGF-β, which encourages the bone microenvironment to evolve. The model is used to explore several potential therapeutic strategies, with some potential drug targets showing more promise than others: in particular, completely blocking Wnt and greatly increasing DKK-1 had significant positive effects, while blocking RANKL did not improve the outcome.

An integrative model of prostate cancer interaction with the bone microenvironment.

Overcoming drug resistance is critical for increasing the survival rate of prostate cancer (PCa). Docetaxel is the first cytotoxic chemotherapeutical approved for treatment of PCa. However, 99% of PCa patients will develop resistance to docetaxel within 3 years. Understanding how resistance arises is important to increasing PCa survival.

Transcription factor network analysis based on single cell RNA-seq identifies that Trichostatin-a reverses docetaxel resistance in prostate Cancer.

The purpose of this review is to summarize the recently published findings regarding the role of epithelial to mesenchymal transition (EMT) in tumor progression, macrophages in the tumor microenvironment, and crosstalk that exists between tumor cells and macrophages.

Article	Year
Anabolic actions of parathyroid hormone during bone growth are dependent on c-fos. Endocrinology\| PubMed ID: 12239115	2002
Translational progress on tumor biomarkers. Thoracic cancer\| PubMed ID: 26557902	2015
Targeting the Notch signaling pathway in cancer therapeutics. Thoracic cancer\| PubMed ID: 26767041	2014
An integrative model of prostate cancer interaction with the bone microenvironment. Mathematical biosciences\| PubMed ID: 28919575	2017
Transcription factor network analysis based on single cell RNA-seq identifies that Trichostatin-a reverses docetaxel resistance in prostate Cancer. BMC cancer\| PubMed ID: 34879849	2021
The Role of Tumor Epithelial-Mesenchymal Transition and Macrophage Crosstalk in Cancer Progression. Current osteoporosis reports\| PubMed ID: 36848026	2023

Evan T. Keller

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