molecular-profiling-invasive-tumor-microenvironment-3-dimensional

Molecular Profiling of the Invasive Tumor Microenvironment in a 3-Dimensional Model of Colorectal Cancer Cells and <em>Ex vivo</em> Fibroblasts

Invading colorectal cancer (CRC) cells have acquired the capacity to break free from their sister cells, infiltrate the stroma, and remodel the ...

University of Southampton School of Medicine

The transcription factor p53 lies at the center of a protein network that controls cell cycle progression and commitment to apoptosis. p53 is inactive in proliferating cells, largely because of negative regulation by the Hdm2/Mdm2 oncoprotein, with which it physically associates. Release from this negative regulation is sufficient to activate p53 and can be triggered in cells by multiple stimuli through diverse pathways. This diversity is achieved in part because Hdm2 uses multiple mechanisms to inactivate p53; it targets p53 for ubiquitination and degradation by the proteosome, shuttles it out of the nucleus and into the cytoplasm, prevents its interaction with transcriptional coactivators, and contains an intrinsic transcriptional repressor activity. Here we show that Hdm2 can also repress p53 activity through the recruitment of a known transcriptional corepressor, hCtBP2. This interaction, and consequent repression of p53-dependent transcription, is relieved under hypoxia or hypoxia-mimicking conditions that are known to increase levels of intracellular NADH. CtBP proteins can undergo an NADH-induced conformational change, which we show here results in a loss of their Hdm2 binding ability. This pathway represents a novel mechanism whereby p53 activity can be induced by cellular stress.

Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription.

CtBP1 and CtBP2 are transcriptional co-repressors that modulate the activity of a large number of transcriptional repressors via the recruitment of chromatin modifiers. Many CtBP-regulated proteins are involved in pathways associated with tumorigenesis, including TGF-beta and Wnt signalling pathways and cell cycle regulators such as RB/p130 and HDM2, as well as adenovirus E1A. CtBP1 and CtBP2 are highly similar proteins, although evidence is emerging that their activity can be differentially regulated, particularly through the control of their subcellular localisation. CtBP2s from diverse species contain a unique N-terminus, absent in CtBP1 that plays a key role in controlling the nuclear-cytoplasmic distribution of the protein.

Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins.

Advances in surgical practice have helped expand the options for patients with locally recurrent rectal cancer through improvements in reconstructive options, management of operative complications, addition of intraoperative adjuvant therapies, and postoperative care. This review outlines the presentation and management of patients with locally recurrent rectal cancer, and it describes easy-to-apply clinical algorithms to aid management.

Clinical algorithms for the surgical management of locally recurrent rectal cancer.

Laparoscopic liver resection (LLR) is now considered a feasible alternative to open liver resection (OLR) in selected patients. Nevertheless studies comparing LLR and OLR are few and concerns remain about long-term oncological equivalence. The present study compares outcomes with LLR vs. OLR using meta-analytical methods.

Short- and long-term outcomes after laparoscopic and open hepatic resection: systematic review and meta-analysis.

The precise contribution of IORT to the management of locally advanced and recurrent colorectal cancer (CRC) remains uncertain. We performed a systematic review and meta-analysis to assess the value of IORT in this setting.

Article	Year
Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription. Current biology : CB\| PubMed ID: 12867035	2003
Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins. BMC cell biology\| PubMed ID: 16999872	2006
Clinical algorithms for the surgical management of locally recurrent rectal cancer. Diseases of the colon and rectum\| PubMed ID: 20706067	2010
Short- and long-term outcomes after laparoscopic and open hepatic resection: systematic review and meta-analysis. HPB : the official journal of the International Hepato Pancreato Biliary Association\| PubMed ID: 21492329	2011
Intraoperative radiotherapy in colorectal cancer: systematic review and meta-analysis of techniques, long-term outcomes, and complications. Surgical oncology\| PubMed ID: 23270946	2013

Alexander H. Mirnezami

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