Medicine (RMH) - Theses
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ItemThe role of myeloid cells in breast cancer metastasis( 2012)Metastasis is the leading cause of death in breast cancer patients. The current methods for predicting likelihood of metastasis are insufficient and treatment options are limited once distant metastasis occurs. Emerging data implicate myeloid cells as active participants in breast cancer metastasis. Myeloid cells in cancer are often studied as Gr-1+CD11b+ myeloid derived suppressor cells. However, this group of cells is comprised of many different cell types, including macrophages and neutrophils. Tumour-associated macrophages (TAMs) can play key roles in metastatic events but little is known about the roles of monocytes, i.e. macrophage precursors, in metastasis, and it has been suggested that monocyte/macrophage subpopulations may have different functions in breast tumour metastasis. Recent data link tumour-associated neutrophils (TANs) to the progression of malignancy in other cancers, but the link between TANs and breast cancer metastasis has not been well studied. This thesis is the first body of work to include a comprehensive analysis of monocytes/macrophages/TAMs and neutrophils/TANs during various stages of mammary tumour metastasis. Utilising three isogenic murine mammary tumour variants, namely 4T1.2 (highly metastatic), 66cl4 (weakly metastatic) and 67NR (non-metastatic), as well as the myeloid cell markers Ly6C (a marker for monocytes and neutrophils) and Ly6G (a marker for neutrophils), it was found that increases in both primary tumour Ly6Clow (non-classical, mature) TAM and TAN numbers, as well as that of circulating Ly6Chigh (classical, immature) monocytes and neutrophils were associated with metastasis. Furthermore, increases in these cells occurred early during tumour progression. Pro-MMP-9 was increased in the serum around this time; hence a model is proposed where increased production of MMP-9, either from the tumour or from the surrounding stroma, enhances mobilisation of monocytes and neutrophils leading to increased TAM and TAN numbers that promote metastasis. Furthermore, preliminary data indicate that co-injection of either TAMs and TANs isolated from highly metastatic tumours may promote the growth of less metastatic tumours. Colony stimulating factor-1 (CSF-1/M-CSF), a key macrophage growth factor, has been implicated in advanced breast cancer. Since inhibition of CSF-1 receptor (CSF-1R) signalling depletes TAMs and reduces metastasis in some mammary tumour models, CSF-1 and CSF-1R are considered targets for the treatment of metastatic disease. It is shown in this thesis, for the first time, that treatment of 4T1.2 tumour-bearing mice with neutralising anti-CSF-1R antibody can increase metastasis to lung and bone, without altering primary tumour growth. Furthermore, CSF-1R blockade leads to increased neutrophils in the primary tumour, metastasis-associated lung and peripheral blood, as well as to increased ‘classical’ Ly6Chigh blood monocytes. These data indicate that neutrophils can also play a critical role in 4T1.2 tumour metastasis. In support of this, it was found that increased expression of a key neutrophil CSF, G-CSF, in weakly metastatic primary tumours enhances circulating neutrophil and Ly6Chigh monocytes and is associated with increased metastasis. Thus, cellular changes in neutrophils and Ly6Chigh monocytes may be linked to metastasis and their subsequent increase upon anti-CSF-1R treatment may be related to the enhanced metastasis observed. The above data indicate that both macrophages and neutrophils may be involved during the early stages of breast tumour metastasis. Further analysis of monocyte/macrophage/TAM subpopulations, as well as neutrophils/TANs, may lead to improved treatment of aggressive breast tumours. Targeting both macrophages and neutrophils may be required for successful treatment of certain breast tumour subtypes. It may also be important to target monocytes and neutrophils both in the circulation and at metastatic sites and, if possible, during early stages of metastasis. Stratification of patients based on primary tumour TAM or TAN numbers may better predict the likelihood of metastasis and also guide treatment strategies.