Thomas R. Cox, Jan 2018
Established Models and New Paradigms for Hypoxia-Driven Cancer-Associated Bone Disease
Our new review on the how hypoxia is important in cancer-associated bone disease has just been published in Calcified Tissue International.
What is Hypoxia and why is it important in cancer?
Hypoxia is the deficiency of oxygen that commonly occurs within tumours. There are two broad classes of hypoxia, transient hypoxia which is associated with inadequate blood flow, while chronic hypoxia is the consequence of the increased oxygen diffusion distance due the rate of tumour growth exceeding the rate of neovascularisation.
Both types of hypoxia are clinically correlated with poor outcome for patients. The presence of hypoxia and the lack of vascularisation represent a double-edged sword of stimuli for cancer progression and obstacles against cancer treatment.
In this review we discuss the importance of hypoxia in both primary and secondary tumours of the bone.
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.
Cox TR, Erler JT and Rumney RMH. Established Models and New Paradigms for Hypoxia-Driven Cancer-Associated Bone Disease
Calcified Tissue International (2017) | doi:10.1007/s00223-017-0352-6
Cancer, Hypoxia, Bone, Metastasis, Lysyl Oxidase