Dataset Information

Linearly Patterned Programmed Cell Necrosis Induced by Chronic Hypoxia Plays a Role in Melanoma Angiogenesis.

ABSTRACT:

Background

Highly aggressive tumors are exposed to hypoxia and increased tumor interstitial fluid pressure (IFP) conditions which is resistant to blood supply. Physiological responses of the organism may reduce IFP through induction of orderly cell death.

Specific aims

This study demonstrates that orderly cell death provided spatial structure for early angiogenesis in the hypoxic, high-IFP tumor microenvironment and the participation of linearly patterned programmed cell necrosis (LPPCN) in nascent melanoma angiogenesis.

Methods

Animal model, laser capture microdissection, wound healing and transwell assays, three-dimensional cultures, zymography assays, western-blotting analysis, immunohistochemistry and RT-PCR were performed.

Results

This study demonstrated a special form of cell death occurring in groups of malignant tumor cells which arrayed in lines. Both features of apoptosis and necrosis can be found in this cell death pattern and were termed as LPPCN. Its role as a stimulus of tumor angiogenesis was investigated using human melanoma samples and an animal model. Computer image analysis showed that LPPCN and tumor microvessels had identical spatial distributions. It can be induced by chronic hypoxia, high IFP and subsequent calcium influx. Higher number of tumor associated macrophages (TAM) and VEGF expression were found in the tumor with LPPCN. Based on the tumor-bearing animal model, it was found that block of caspase pathway inhibited LPPCN, microvessel density and vasculogenic mimicry (VM).

Conclusions

LPPCN formation may play an important role in tumor angiogenesis due to stimulation of macrophage infiltration and HIF-1? regulation, and that inhibition of LPPCN may be a novel therapeutic strategy against tumor angiogenesis and metastasis.

SUBMITTER: Zhao X

PROVIDER: S-EPMC4679377 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Linearly Patterned Programmed Cell Necrosis Induced by Chronic Hypoxia Plays a Role in Melanoma Angiogenesis.

Zhao Xiulan X Sun Baocun B Liu Yanrong Y Zhang Danfang D Liu Zhiyong Z Zhao Xueming X Gu Qiang Q Han Chunrong C Dong Xueyi X Che Na N An Jindan J Zheng Yanjun Y Liu Tieju T

Journal of Cancer 20160101 1

<h4>Background</h4>Highly aggressive tumors are exposed to hypoxia and increased tumor interstitial fluid pressure (IFP) conditions which is resistant to blood supply. Physiological responses of the organism may reduce IFP through induction of orderly cell death.<h4>Specific aims</h4>This study demonstrates that orderly cell death provided spatial structure for early angiogenesis in the hypoxic, high-IFP tumor microenvironment and the participation of linearly patterned programmed cell necrosis ...[more]

PMID: 26722356

Similar Datasets

Project description:Positron emission tomography (PET) using 18F-fluoromisonidazole (FMISO) is a promising technique for imaging tumour hypoxia, and a potential target for radiotherapy dose-painting. However, the relationship between FMISO uptake and oxygen partial pressure ([Formula: see text]) is yet to be quantified fully. Tissue oxygenation varies over distances much smaller than clinical PET resolution (<100 ?m versus???4?mm), and cyclic variations in tumour perfusion have been observed on timescales shorter than typical FMISO PET studies (?20?min versus a few hours). Furthermore, tracer uptake may be decreased in voxels containing some degree of necrosis. This work develops a computational model of FMISO uptake in millimetre-scale tumour regions. Coupled partial differential equations govern the evolution of oxygen and FMISO distributions, and a dynamic vascular source map represents temporal variations in perfusion. Local FMISO binding capacity is modulated by the necrotic fraction. Outputs include spatiotemporal maps of [Formula: see text] and tracer accumulation, enabling calculation of tissue-to-blood ratios (TBRs) and time-activity curves (TACs) as a function of mean tissue oxygenation. The model is characterised using experimental data, finding half-maximal FMISO binding at local [Formula: see text] of 1.4 mmHg (95% CI: 0.3-2.6 mmHg) and half-maximal necrosis at 1.2 mmHg (0.1-4.9 mmHg). Simulations predict a non-linear non-monotonic relationship between FMISO activity (4?hr post-injection) and mean tissue [Formula: see text] : tracer uptake rises sharply from negligible levels in avascular tissue, peaking at???5 mmHg and declining towards blood activity in well-oxygenated conditions. Greater temporal variation in perfusion increases peak TBRs (range 2.20-5.27) as a result of smaller predicted necrotic fraction, rather than fundamental differences in FMISO accumulation under acute hypoxia. Identical late FMISO uptake can occur in regions with differing [Formula: see text] and necrotic fraction, but simulated TACs indicate that additional early-phase information may allow discrimination of hypoxic and necrotic signals. We conclude that a robust approach to FMISO interpretation (and dose-painting prescription) is likely to be based on dynamic PET analysis.

Dataset Information

Linearly Patterned Programmed Cell Necrosis Induced by Chronic Hypoxia Plays a Role in Melanoma Angiogenesis.

Background

Specific aims

Methods

Results

Conclusions

Publications

Linearly Patterned Programmed Cell Necrosis Induced by Chronic Hypoxia Plays a Role in Melanoma Angiogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets