Bidirectional effect of CD200 on breast cancer development and metastasis, with ultimate outcome determined by tumor aggressiveness and a cancer-induced inflammatory response

Abstract

CD200 acts through its receptor (CD200R) to inhibit excessive inflammation. The role of CD200-CD200R1 interaction in tumor immunity is poorly understood. In this study, we examined the role of CD200-CD200R1 interaction in the progression and metastasis of highly aggressive 4THM murine-breast carcinoma using CD200 transgenic (CD200(tg)) and CD200R1 knock-out (CD200R1(-)(/-)) BALB/c mice. 4THM cells induce extensive visceral metastasis and neutrophil infiltration in affected tissues. CD200 overexpression in the host was associated with decreased primary tumor growth and metastasis, whereas lack of CD200R1 expression by host cells was associated with enhanced visceral metastasis. Absence of CD200R1 expression led to decreased tumor-infiltrating-cytotoxic T cells and increased the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. In contrast, CD200 overexpression led to increased tumor-induced interferon-γ and IL-10 response and decreased TNF-α and IL-6 release. Neutrophil infiltration of tissues was markedly decreased in CD200(tg) animals and increased in CD200R1(-/-) mice. These findings are contradictory to what has been reported in the EMT6 mouse breast-cancer model. Other distinguishing features of tumor elicited by EMT6 and 4THM cell injections were also examined. Visceral tissues from mice bearing EMT6 tumors showed a lack of neutrophil infiltration and decreased IL-6 release in CD200R1(-/-) mice. EMT6 and 4THM cells also differed in vimentin expression and in vitro migration rate, which was markedly lower in EMT6 tumors. These results support the hypothesis that CD200 expression can alter immune responses, and can inhibit metastatic growth of tumor cells that induce systemic and local inflammatory response. Increasing CD200 activity/signaling might be an important therapeutic strategy for treatment of aggressive breast carcinomas.

A Critical Role for CD200R Signaling in Limiting the Growth and Metastasis of CD200+ Melanoma

“…However, the results from these studies are more mixed, and none of these studies used the more aggressive mouse melanoma model. Thus, the discrepancy of previously published results with this study suggests that the role of CD200 in tumor immunity may differ in different tumor types (41), and may be associated with the tumor aggressiveness and its ability to induce inflammation, as suggested by a recent study (42) using CD200R-deficient mice.…”

Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade

“…Murine 4T1 cells were originally isolated from a spontaneous mammary tumour in the BALB/c strain and have been reported as metastatic and also exhibit the characteristics of human basal/triple-negative breast cancer (TNBC) subtype14. In contrast, the EMT6 and 67NR murine cell lines have been shown to be less invasive1516. We first verified the tumorigenic and metastatic ability of EMT6 and 4T1 tumours, when 50,000 cells from both lines were injected into the mammary fat pads of, they produced similarly sized tumours within 8 weeks (Fig.…”

CXCL8, IL-1β and sCD200 are pro-inflammatory cytokines and their levels increase in the circulation of breast carcinoma patients

“…Genetically engineered mice that overexpressed CD200 showed that the metastatic growth of breast tumor cells increased (14). By contrast, highly aggressive, but similar, breast carcinoma cells had decreased metastatic growth in a CD200-overexpressed host (16). These two opposing effects may be explained by the bidirectional characteristic of CD200.…”

“…The role of CD200 in breast cancer progression and metastasis has been studied in animal breast carcinoma model, where CD200 overexpression resulted in increased lymph node metastasis (14). By contrast, CD200 expression by melanocytes resulted in decreased lung metastasis (15) and decreased metastatic growth of breast carcinoma cells (16). Thus far, sCD200 has not been studied on human breast carcinoma subjects.…”