Necrosis | EPFL Graph Search

Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal. Cellular death due to necrosis does not follow the apoptotic signal transduction pathway, but rather various receptors are activated and result in the loss of cell membrane integrity and an uncontrolled release of products of cell death into the extracellular space. This initiates in the surrounding tissue an inflammatory response, which attracts leukocytes and nearby phagocytes which eliminate the dead cells by phagocytosis. However, microbial damaging substances released by le

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors

Anne Planche, Tania Santoro

Background: Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study. Methods: Cancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis. Results: Exposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment. Conclusions: Taken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy.

Biomed Central Ltd2016

Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis

Michele De Palma, Francine Jordan, Mario Leonardo Squadrito

PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion. We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2(+/-) mice was due to an expansion of tissue-resident, M2-like macrophages and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2(+/-) macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.

2011

Optimization of the Distance between Cylindrical Light Distributors Used for Interstitial Light Delivery in Biological Tissues

Aurelien Stephen Arnaud Gregor, Georges Wagnières

Cylindrical light diffusers (CLDs) are often employed for the treatment of large tumors by interstitial photodynamic therapy (iPDT) and photoimmunotherapy (PIT), which involves careful treatment planning to maximize therapeutic dose coverage while minimizing the number of CLDs used. There is, however, a lack of general guidelines regarding optimal positioning of CLDs, in particular when they are inserted in parallel to treat head and neck squamous cell cancer (HNSCC). Therefore, the purpose of this study is to determine the CLD-CLD distances maximizing the necrosis for different geometries of CLD positions and shed light on the influence of different optical parameters on this distance, in particular when HNSCCs are treated by interstitial PIT with cetuximab-IR700 using up to seven CLDs. To that end, Monte-Carlo simulations of the light propagation around CLDs inserted perpendicularly in a semi-infinite tumor were performed to determine the volume receiving a fluence larger than a therapeutic threshold. An optimization algorithm was then used to calculate and maximize the necrosed tumor volumes. Tumor optical properties were derived from published data. Our findings suggest that optimal CLD positioning maximizing the volume of necrosed tumor during interstitial PIT for typical HNSCC optical properties corresponds to a CLD-CLD distance between 11.5- and 13-mm. Variations of the absorption and reduced scattering coefficients have the greatest influence on CLD placements, while tissue anisotropy factor, CLD insertion geometry, CLD length, and the angular dependence of the radiance emitted by the CLDs have minimal influence. At first approximation the influence of these optical parameters on optimal CLD-CLD distance are independent. Our data also suggests it is possible to derive new treatment plans using knowledge of previous treatment plans.

MDPI2022