The five-year survival rate for primary bone
cancers is ~ 70% while almost all cases of secondary metastatic
bone cancer are terminal.
Hypoxia, the deficiency of
oxygen which occurs as the rate of tumour growth exceeds the supply of vascularisation, is a key promoter of tumour progression.
Hypoxia-driven effects in the primary tumour are wide ranging including changes in gene expression, dysregulation of signalling pathways, resistance to
chemotherapy, neovascularisation, increased tumour cell proliferation and migration. Paget's seed and soil theory states that for a metastasising tumour cell 'the seed' it requires the correct microenvironment 'soil' to colonise. Why and how metastasising tumour cells colonise the bone is a complex and intriguing problem. However, once present tumour cells are able to disrupt bone homeostasis through increasing osteoclast activity and downregulating osteoblast function. Osteoclast resorption releases
growth factors from the bone matrix that subsequently contribute to the proliferation of invasive tumour cells creating the vicious cycle of bone loss and metastatic
cancer progression. Recently, we have shown that
hypoxia increases expression and release of
lysyl oxidase (LOX) from primary mammary tumours, which in turn disrupts bone homeostasis to favour osteolytic degradation to create pre-metastatic niches in the bone microenvironment. We also demonstrated how treatment with
bisphosphonates could block this
cancer-induced bone remodelling and reduce secondary bone
metastases. This review describes the roles of
hypoxia in primary tumour progression to
metastasis, with a focus on key signalling pathways and treatment options to reduce patient morbidity and increase survival.