Breast cancer as a systemic disease: a view of metastasis

Abstract

Breast cancer is now the most frequently diagnosed cancer and leading cause of cancer death in women worldwide. Strategies targeting the primary tumour have markedly improved, but systemic treatments to prevent metastasis are less effective; metastatic disease remains the underlying cause of death in the majority of patients with breast cancer who succumb to their disease. The long latency period between initial treatment and eventual recurrence in some patients suggests that a tumour may both alter and respond to the host systemic environment to facilitate and sustain disease progression. Results from studies in animal models suggest that specific subtypes of breast cancer may direct metastasis through recruitment and activation of haematopoietic cells. In this review, we focus on data implicating breast cancer as a systemic disease.

Keywords: breast cancer; disseminated tumour cells; metastasis; systemic instigation; tumour dormancy; tumour microenvironment.

Fig. 1

Fig. 1A. Model of systemic instigation by luminal breast cancer Using our preclinical model, we demonstrated that in hosts with luminal breast cancer, otherwise indolent tumour cells implanted at distant anatomical sites develop into an actively growing tumour. The responding tumour growth is stimulated by pro-angiogenic platelets and bone marrow-derived VEGFR2-positive cells that are recruited to the responding tumour site. As a consequence of this systemic cascade, the responding tumour stroma becomes highly vascularized, and the tumour cells become enriched in the cell-surface marker CD24, a ligand for platelet-specific p-selectin. Of note, this process is distinct from the growth of responding tumours in hosts with triple-negative breast cancer (see Fig. 1B). Fig. 1B. Model of systemic instigation by triple-negative breast cancer In hosts with triple-negative breast cancer, otherwise indolent tumour cells implanted at a distant anatomical site develop into an actively growing tumour. Instigating triple-negative breast tumours secrete osteopontin (OPN) and other cytokines into the circulation; this subsequently mobilizes a distinct subpopulation of bone marrow cells characterized by Sca1+/cKit−/CD45+ and granulin (GRN) expression. After trafficking to the responding tumour site, these bone marrow-derived cells activate cancer-associated fibroblasts that support tumour growth.

Fig. 1

Fig. 1A. Model of systemic instigation by luminal breast cancer Using our preclinical model, we demonstrated that in hosts with luminal breast cancer, otherwise indolent tumour cells implanted at distant anatomical sites develop into an actively growing tumour. The responding tumour growth is stimulated by pro-angiogenic platelets and bone marrow-derived VEGFR2-positive cells that are recruited to the responding tumour site. As a consequence of this systemic cascade, the responding tumour stroma becomes highly vascularized, and the tumour cells become enriched in the cell-surface marker CD24, a ligand for platelet-specific p-selectin. Of note, this process is distinct from the growth of responding tumours in hosts with triple-negative breast cancer (see Fig. 1B). Fig. 1B. Model of systemic instigation by triple-negative breast cancer In hosts with triple-negative breast cancer, otherwise indolent tumour cells implanted at a distant anatomical site develop into an actively growing tumour. Instigating triple-negative breast tumours secrete osteopontin (OPN) and other cytokines into the circulation; this subsequently mobilizes a distinct subpopulation of bone marrow cells characterized by Sca1+/cKit−/CD45+ and granulin (GRN) expression. After trafficking to the responding tumour site, these bone marrow-derived cells activate cancer-associated fibroblasts that support tumour growth.