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The work carried out investigating TJs over recent years indicates that this is an area of great interest as targets for cancer diagnosis and potential therapeutics. From the work outlined in section 4, it can be seen that changes in TJ molecule expression, such as occludin, claudin-1, claudin-2, claudin-3, claudin-4, claudin-5, claudin-7, and MAGUK proteins ZO-1, ZO-2, and MUPP-1. These provide potential prognostic indicators for breast tumours. The claudin family has caused considerable interest as an emerging target for cancer therapy (61); however, it remains to be seen how much of this potential can be translated into real treatments. Interestingly, levels of CAR have been found to be significantly correlated with long-term survival of patients with breast cancer with total CAR levels being elevated in primary breast cancers (132). This may have a bearing on its use as means of delivery for gene therapy.

Agents that inhibit the effects of cytokines and growth factors such as TNF-a, TGF-ß, VEGf, and HGF, all of which are able to decrease tran-sepithelial/transendothelial resistance and increase paracellular permeability, as well as promote cell-cell dissociation, invasion, and spread could be useful tools in the fight against breast cancer metastasis. It has been shown that the HGF variant NK4 is able to successfully inhibit HGF induced decrease in both epithelial and endothelial cell TJ function (133). Moreover, other less likely substances appear to have profound effects on the inhibition of TJ disruptive elements such as estrogen. Disruption of TJs in endothelial and epithelial cells can lead to leaky vascular bed and potentially to oedema and swelling of tissues, the aetiology of mastalgia, and a potential means of escape for tumour cells from the primary tumour. A recent study aimed to determine whether the function of TJs in endothelial cells can be strengthened by gamma linolenic acid (GLA), selenium (Se), and iodine (I) in the presence of 17beta estradiol (17beta estradiol), which causes leakage of endothelial cells by disrupt-tion of TJs in endothelium (134). GLA, I, and Se individually increased transendothelial resistance. The combination of all three agents also had a significant effect. Addition of GLA/Se/I reduced paracellular permeability of the endothelial cells. Treatment with GLA/Se/I reversed the effect of 17beta estradiol in reducing resistance and increasing permeability. Immunofluorescence revealed that after treatment with Se/I/GLA over 24 hours there was increasing relocation to endothelial cell-cell junctions of the TJs proteins claudin-5, occludin, and ZO-1. Interestingly, this relocation was particularly evident with treatments containing I when probing with claudin-5 and those containing Se for occludin. There was a small increase in overall protein levels after treatment with GLA/Se/I when probed with claudin-5 and occludin. GLA, I, and Se alone, or in combination are able to strengthen the function of TJs in human endo-thelial cells, by way of regulating the distribution of claudin-5, occludin, and ZO-1. Interestingly, this combination was also able to completely reverse the effect of 17beta estradiol in these cells.

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