This section aims at providing more information on topics that were addressed briefly in other sections.
Tumour Associated Macrophages
Tumour associated macrophages (TAMs) are peripheral monocytes that reside in the tumour. TAMs encourage tumour growth, angiogenesis and metastasis through reduced cytokine production. Willingham et al (2012) demonstrated that upon the inhibition of CD47-SIRPα pathway in bladder, liver and breast cancer, the magnitude of phagocytosis increased. This suggests that the tumour-supportive TAMs were converted to activated macrophages that phagocytose malignant cells.
The role of CD47 in normal cells
Although CD47 is overexpressed on the surfaces of cancer cells, it serves a number of functions in normal physiology as well:
- Regulation of integrin-dependent mechanisms, e.g. cell adhesion and migration (Rebres et al, 2005)
- In vitro and in vivo studies have elucidated the role of CD47 in neutrophil recruitment and leukocyte adhesion to the endothelium in host defence (Oldenborg et al, 2000).
- Regulation of platelet aggregation through interactions with thrombospondin-1 (Isenberg et al, 2008)
- Determines lifespan of red blood cells and platelets through inhibition of phagocytosis via splenic macrophages as shown in Figure 9
- Neurite formation and branching (Matosaki et al, 2009)
- Interacts with SIRPα to promote formation of filopodia on dendrites (Matosaki et al, 2009)
- Synaptic plasticity and memory formation in the hippocampus (Matosaki et al, 2009)
- Negatively regulates T cells in type 1 immune responses (Bouguermouh et al, 2008)
Calreticulin: why anti-CD47 antibody treatment does not affect normal cells
Normal cells also express CD47 but they are not engulfed by macrophages in the presence of anti-CD47 antibody because additional pro-phagocytic signal is required. The surface of cancerous cells express a protein called calreticulin. It is this protein that serve as a pro-phagocytic signal by binding to a macrophage receptor resulting in its engulfment. It is for this reason why cancer cells express CD47 to protect against calreticulin medicated phagocytosis. In other words, calreticulin is the primary pro-phagocytic signal and is counteracted by the signaling pathways of CD47. This provides an explanation on why the tumour cells were selectively targeted during anti-CD47 antibody therapy.