Abstract:
:The abundance of macrophages is an independent negative prognostic factor in a range of cancer types, linked to the actions of macrophage products on vasculogenesis and cancer cell survival, motility and metastasis. TNF-α is a macrophage product and a product of some cancer cell types that is also associated with adverse prognosis in clinical and experimental cancers, through enhanced tumour cell growth, survival and metastasis. Macrophages are important targets of TNF-α. We observed that TNF-α partly substituted for the macrophage growth factor, M-CSF, in maintaining macrophage survival by protecting cells from apoptosis. We found that TNF-α afforded similar protection to chemotherapeutic agents and related cytotoxic drugs that acted through a range of apoptosis-initiating pathways, but not where protein synthesis was inhibited. Protection was dependent on intact NF-κB signalling. In addition to NF-κB-dependent factors previously identified as anti-apoptotic, we found an absolute requirement for very early antagonism of mitochondrial cytochrome C release, which sufficed to prevent apoptosis in the face of activation of a range of upstream apoptosis pathways, including p53, DISC-linked, mitochondrial depolarisation and calcium-sensitive pathways. The capacity of TNF-α to preserve macrophage numbers in the face of chemotherapy drugs is a potential contributor to prognosis in TNF-α-expressing cancers, encouraging further testing of anti-TNF-α treatments in these patients.
journal_name
Cancer Lettjournal_title
Cancer lettersauthors
Lo SZY,Steer JH,Joyce DAdoi
10.1016/j.canlet.2011.03.020subject
Has Abstractpub_date
2011-08-01 00:00:00pages
80-92issue
1eissn
0304-3835issn
1872-7980pii
S0304-3835(11)00181-9journal_volume
307pub_type
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