Abstract
Simple SummaryUsing a mouse model of breast cancer driven by the mammary epithelial expression of the polyoma middle T oncoprotein in which the tumors progress from benign to malignant metastatic stages, we show that cancer causes an increase in circulating monocytes and a splenomegaly. This increase in monocyte number is due to their increased proliferation in the bone marrow and not turnover rates in the blood. Single cell sequencing also shows that new populations of monocytes do not arise during cancer. Cancer also drives systemic changes in the monocyte transcriptome, with a notable down-regulation of interferon signaling. These systemic influences start in the bone marrow but intensify in the blood. Comparison of cancer prone and cancer resistant mouse inbred strains carrying the same oncogene reveals that the genetic background of the strain causes different monocyte transcriptional changes. Similarly, a comparison of the mouse transcriptome to human breast cancer monocyte profiles indicates limited similarities, to the extent that interferon signaling is enhanced in humans. Systemic responses are different in the same model of cancer on different genetic backgrounds within a species and even greater changes are found across species. These data suggest that at the very least this mouse model will be limited when it comes to exploring the mechanism behind systemic changes in humans.There is a growing body of evidence that cancer causes systemic changes. These influences are most evident in the bone marrow and the blood, particularly in the myeloid compartment. Here, we show that there is an increase in the number of bone marrow, circulating and splenic monocytes by using mouse models of breast cancer caused by the mammary epithelial expression of the polyoma middle T antigen. Cancer does not affect ratios of classical to non-classical populations of monocytes in the circulation nor does it affect their half-lives. Single cell RNA sequencing also indicates that cancer does not induce any new monocyte populations. Cancer does not change the monocytic progenitor number in the bone marrow, but the proliferation rate of monocytes is higher, thus providing an explanation for the expansion of the circulating numbers. Deep RNA sequencing of these monocytic populations reveals that cancer causes changes in the classical monocyte compartment, with changes evident in bone marrow monocytes and even more so in the blood, suggesting influences in both compartments, with the down-regulation of interferon type 1 signaling and antigen presentation being the most prominent of these. Consistent with this analysis, down-regulated genes are enriched with STAT1/STAT2 binding sites in their promoter, which are transcription factors required for type 1 interferon signaling. However, these transcriptome changes in mice did not replicate those found in patients with breast cancer. Consequently, this mouse model of breast cancer may be insufficient to study the systemic influences of human cancer.
Highlights
Monocytes are key players in the innate immune system, surveying the vasculature in the steady state or being recruited to normal tissues and to sites of infection or tissue damage where they terminally differentiate into macrophages and dendritic cells [1]
The effects of cancer on monocytes and neutrophils were determined in the blood, bone marrow (BM), and spleen using the polyoma middle T mouse model of breast cancer on a BL6 genetic background
Expression to distinguish monocytes (CD115high ) from neutrophils (Ly6G+ ), we found that both monocytes and neutrophils increased in numbers even in control mice with age, but this effect was greater in late cancers and accounted for most if not all of the expansion of CD11b+ cells (Figure 1D,E)
Summary
Monocytes are key players in the innate immune system, surveying the vasculature in the steady state or being recruited to normal tissues and to sites of infection or tissue damage where they terminally differentiate into macrophages and dendritic cells [1]. The current consensus is that blood monocytes largely derive from hematopoietic stems cells (HSC) in the bone marrow (BM). These progenitors differentiate through several steps to give the restricted erythro-myeloid progenitors that are present in the more abundant. This bi-potent progenitor differentiates to a macrophage dendritic cell progenitor (MDP) and, subsequently, the unipotent monocyte progenitor (cMoP) [2]. There are two dominant blood populations, the classical (Ly6Chi CCR2hi and CD14hi CCR2hi CD16− respectively) and non-classical populations (Ly6Clo CCR2− and CD16hi CCR2− CD14dim respectively) [7,8], with an intermediate population with mixed markers (Ly6Cmid and CD14hi CD16hi respectively) [9,10]. The ratio of monocytes in steady state conditions is different in mice and humans, with the former having almost equal numbers of the two populations and the classical subset predominating in the latter
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