State of the Art Modelling of the Breast Cancer Metastatic Microenvironment: Where Are We?

Abstract

Metastatic spread of tumour cells to tissues and organs around the body is the most frequent cause of death from breast cancer. This has been modelled mainly using mouse models such as syngeneic mammary cancer or human in mouse xenograft models. These have limitations for modelling human disease progression and cannot easily be used for investigation of drug resistance and novel therapy screening. To complement these approaches, advances are being made in ex vivo and 3D in vitro models, which are becoming progressively better at reliably replicating the tumour microenvironment and will in the future facilitate drug development and screening. These approaches include microfluidics, organ-on-a-chip and use of advanced biomaterials. The relevant tissues to be modelled include those that are frequent and clinically important sites of metastasis such as bone, lung, brain, liver for invasive ductal carcinomas and a distinct set of common metastatic sites for lobular breast cancer. These sites all have challenges to model due to their unique cellular compositions, structure and complexity. The models, particularly in vivo, provide key information on the intricate interactions between cancer cells and the native tissue, and will guide us in producing specific therapies that are helpful in different context of metastasis.

Keywords: Bone; Brain; Breast cancer metastasis; Liver; Lobular breast cancer; Lung.

Fig. 1

Breast Cancer Microenvironment in Bone. The Bone Marrow is a Complex Environment With Various Cell Populations. Vascular Endothelial Cells and Associated Stromal Cells Such As LepR + and NG2 + cells and Pericytes Are Important Regulators of Haematopoietic Stem Cell (HSC) Activity. Osteoblasts Line the Endosteal Surface of the Bone and Also Have Important Roles in HSC Maintenance. These Originate From the Differentiation of MSC. HSC Derive Various Cells Including Macrophages, Megakaryocytes, Dendritic Cells and B and T Cells. These Feedback and Help Regulate HSCs. Other Cells Are Present Such As Nonmyelinating Schwann Cells and Sympathetic Nerves. The Central Bone Marrow Has a Lower Oxygen Tension Than Other Tissues. The Central Bone Marrow is Quite Soft While the Endosteal Region is Stiffer. When Breast Cancer Cells Metastasise to Bone, They Take Advantage of the Various Cytokines Naturally Present in This Environment to Establish Themselves and Proliferate. Tumour Cells Also Undergo Various Changes to Become Better Adapted to the Bone Microenvironment. They Also Disrupt Bone Homeostasis By Stimulating Osteoclastogenesis and Inhibiting Differentiation to Osteoblasts As Well As Their Activity. This Induces the Formation of the Osteolytic Lesions Associated With This Disease. (DKK1 – Dickkopf 1; IGF – insulin-like growth factor; IL – interleukin; LepR + – Leptin receptor positive; M-CSF – macrophage-colony stimulating factor; MMPs – matrix metalloproteinases; NG2 +—neural-glial antigen 2 positive; OMD – Osteomodulin; PDGF – platelet-derived growth factor; PTHRP – parathyroid hormone-related protein; SOST1 – sclerostin; TGFβ1 – Transforming growth factor beta 1; TNF – tumour necrosis factor; VEGF – vascular endothelial growth factor)

Fig. 2

Overview of Different in Vivo, in Vitro, and Ex Vivo Approaches for the Study of Metastatic Microenvironments in Breast Cancer