Macrophage Scavenger Receptor A Promotes Tumor Progression in Murine Models of Ovarian and Pancreatic Cancer

Abstract

Alternatively activated macrophages express the pattern recognition receptor scavenger receptor A (SR-A). We demonstrated previously that co-culture of macrophages with tumour cells upregulates macrophage SR-A expression. We show here that macrophage SR-A deficiency inhibits tumour cell migration in a co-culture assay. We further demonstrate that co-culture of tumour-associated macrophages (TAMs) and tumour cells induces secretion of factors which are recognized by SR-A on TAMs. We tentatively identified several potential ligands for the SR-A receptor in tumour cell – macrophage co-cultures by mass spectrometry. Competing with the co-culture induced ligand in our invasion assay recapitulates SR-A deficiency and leads to similar inhibition of tumour cell invasion. In line with our in vitro findings, tumour progression and metastasis is inhibited in SR-A-/- mice in two in vivo models of ovarian and pancreatic cancer. Finally, treatment of tumour-bearing mice with 4F, a small peptide SR-A ligand able to compete with physiological SR-A ligands in vitro, recapitulates the inhibition of tumour progression and metastasis observed in SR-A-/- mice. Our observations suggest that SR-A may be a potential drug target in the prevention of metastatic cancer progression.

Apolipoprotein A-I: A Molecule of Diverse Function

“…Not only that, apo A-I also causes decline in survivin, an inhibitor of apoptosis and cell cycle promoter, responsible for recurrence and reduced survival in melanoma, as shown by Piras et al [47] (Fig. 4) [15,43,47].…”

“…Their number increases both within and outside the tumor, in response to various molecules present within the tumor itself. However, apo A-I also suppresses this increase of MDSCs, both within and outside the tumor and help in tumor regression [15,43]. Not only that, apo A-I also causes decline in survivin, an inhibitor of apoptosis and cell cycle promoter, responsible for recurrence and reduced survival in melanoma, as shown by Piras et al [47] (Fig.…”

“…Tumor-associated macrophages, that form a constant part of the tumor microenvironment in many distinct types of malignancy polarize towards an anti-inflammatory M2 phenotype with expressed scavenger receptor A (SR A), hence promoting tumor progression. However, a change in phenotype expression takes place by apo A-I in the tumor-associated macrophages, from a pro-tumor M2 to an anti-tumor M1 phenotype responsible for tumor rejection, thus helping to establish the therapeutic efficacy of apo A-I against cancers [15,43]. These SR A on macrophages can be therapeutically targeted in vivo with the small peptide inhibitor 4F, a D-amino acid peptide, an apo A-I mimetic, by blocking SRA-mediated macrophage adhesion, and help to prevent tumor progression and distant metastasis.…”

Impact by pancreatic stellate cells on epithelial-mesenchymal transition and pancreatic cancer cell invasion: Adding a third dimension in vitro

“…The major non-malignant cellular components of the tumour microenvironment, the pancreatic stellate cells and tumour-associated macrophages, have been suggested to be involved in the progression of pancreatic cancer by creating a favourable tumour microenvironment and stimulate invasion, tumour growth, and development of metastases (Hwang et al, 2008, Masamune et al, 2008, Neyen et al, 2013, Green et al, 2009 TPSCs such as uPA, FGF and PDGF may likely also be involved (Rosendahl et al, 2015).…”

“…TAMs are frequently found at the tumour periphery where they supply matrix remodelling enzymes and stimulate local invasion. TAMs may also play a role in EMT to facilitate dissemination of tumour cells, and in regulating the local inflammation to block anti-tumour responses (Neyen et al, 2013, Green et al, 2009, Wormann et al, 2014.…”