Bone marrow resident Macs Osteomacs are located in

Bone marrow resident Macs (Osteomacs) are located in canopy-like structures in endosteal and periosteal surfaces, above osteoblasts [6]; osteoclasts result from the fusion of several myeloid osteoclast precursors [7]. Osteomacs constitute approximately 17% of the bone marrow order Octreotide acetate and they differ from osteoclasts by the expression of F4/80 and CD68. In addition, osteomacs play an important role in bone repair and hematopoietic stem cell (HSC) niche maintenance [6].
Tumour-associated macrophages (TAMs) in the bone metastatic cascade In primary breast tumours, 5–40% of the tumour mass consists of TAMs [9]. TAMs often resemble M2 Macs and the majority of the published studies report an association between poor disease outcome and the number of TAMs or low M1/M2 ratio [8]. In some studies, TAMs are associated with good prognosis (e.g., prostate, stomach, colon, cervix, lung and pancreas). However, the M1/M2 ratio or the location of the TAMs might - at least to some extent - explain these favourable outcomes [8]. In order to form bone metastases the cancer cells have to go through several steps, the so-called metastatic cascade. The metastatic cascade includes local invasion of surrounding healthy tissue, intravasation (formation of circulating tumour cells, CTCs), migration and survival in circulation, extravasation (formation of disseminated tumour cells, DTCs), angio- and lymphangiogenesis, matrix remodelling, premetastatic niche formation, survival at the new site either as dormant or proliferating DTCs, dormancy escape, proliferation and macrometastases formation [10]. We and others have recently reviewed the role of TAMs in each of the metastatic steps [11–13].
TAMs\' role in bone metastasis and primary bone cancer: evidence from preclinical and clinical studies The majority of preclinical and clinical studies assess TAMs in primary tumours and metastasis-associated macrophages (MAMs) in visceral metastases (e.g. lung, liver, kidney, spleen, brain). Some preclinical models require long progression times to form bone metastases which might limit their usefulness due to ethical reasons. Nevertheless, there is some indirect evidence of a role for TAMs in bone metastasis arising from studies in cancer models with systemic (Csf1op/op mice), conditional (MaFIA mouse model) or pharmacological macrophage ablation (e.g., the use of clodronate liposomes, CLO-LIP) and from retrospective clinical studies (see Table 1).
TAM targeting therapeutic opportunities Considering every TAM/bone metastasis aspect discussed so far, it is clear that TAMs like many other cells of the tumour microenvironment are almost ideal therapeutic targets, as they are genetically stable, seem to adopt a different polarization in cancer compared to the physiological polarization status in a given tissue, and are recruited and educated by cancer cell secreted factors. Thus, agents targeting recruitment and polarization (e.g., anti-M-CSF antibodies and small molecule inhibitors of M-CSFR and bisphosphonates), M1 activating agents (e.g. mifamurtide, IL-2, zoledronate), agents interfering with the cancer cell/TAM crosstalk (e.g., VCAM-1/α4 integrin inhibition) and Mac depleting agents (e.g., CLO-LIP) are all strategies being pursued, mostly still in the preclinical setting [11]. However, with the ever evolving understanding of the roles of TAMs, it is reasonable to think that in the future TAM modulating therapies might be at the disposal of clinicians and patients.
Outstanding questions
Conflict of interest
Introduction Breast cancer commonly spreads to bone in a process involving migration of tumour cells through the stroma followed by intravasation, homing to and extravasation at distant sites such as bone, and ultimately survival in this new metastatic environment. The survival of tumour cells during this process is influenced by their genetic signature and a plethora of host cells and soluble factors [1]. Disrupting the process of metastatic spread from primary breast tumour to bone was evaluated using the osteoclast inhibitors, bisphosphonates, in (neo)adjuvant clinical trials, with the hypothesis that preventing osteolysis, and release of tumour promoting growth factors from bone, may inhibit tumour cell survival. Bisphosphonates were found to improve survival only in women who were naturally or chemically postmenopausal when treatment was started [2]. The molecular mechanism for this differential effect of bisphosphonates according to menopausal status is currently unknown, but there is evidence that female hormones, such as inhibin, can interact with paracrine factors known to affect tumour cell growth in both the breast primary tumour and the bone microenvironment.