A Mouse Model of Human Breast Cancer Metastasis to Human Bone

Abstract

Currently, an in vivo model of human breast cancer metastasizing from the orthotopic site to bone does not exist, making it difficult to study the many steps of skeletal metastasis. Moreover, models used to identify the mechanisms by which breast cancer metastasizes to bone are limited to intracardiac injection, which seeds the cancer cells directly into the circulation, thus bypassing the early steps in the metastatic process. Such models do not reflect the full process of metastasis occurring in patients. We have developed an animal model of breast cancer metastasis in which the breast cancer cells and the bone target of osteotropic metastasis are both of human origin. The engrafted human bone is functional, based on finding human IgG in the mouse bloodstream, human B cells in the mouse spleen, and normal bone histology. Furthermore, orthotopic injection of a specific human breast cancer cell line, SUM1315 (derived from a metastatic nodule in a patient), later resulted in both bone and lung metastases. In the case of bone, metastasis was to the human implant and not the mouse skeleton, indicating a species-specific osteotropism. This model replicates the events observed in patients with breast cancer skeletal metastases and serves as a useful and relevant model for studying the disease. (Cancer Res 2005; 65(14): 6130-38)

Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation

“…In vivo models have been developed to study breast cancer metastases to bone by means of i.v. and skeletal injection of breast cancer cells in mice (13). Although in vivo models play an essential role in replicating physiological conditions, they lack the possibility to analyze highly specific interactions between human cancer cells, human blood vessels, and tissues, and they are not well suited to perform reproducible parametric studies.…”

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

“…32 Humanized murine models of prostate cancer bone metastases which seek to incorporate a humanized bone marrow niche such as with engineered bone scaffolds seeded with human BM-MSCs, or human fetal or hip bone grafts, or engraftment of human haematopoietic stem cells and BM-MSCs into a murine background may generate predictive preclinical models but these are cumbersome and difficult modeling strategies which are not yet well established. [33][34][35][36] One strategy to demonstrate proof-of-principle implicating a candidate seed-and-soil mechanism in prostate cancer is to use the "clinic as laboratory" model to circumvent the limitations of existing animal models. For example, an early phase clinical study with a potent neutralizing antibody to a5b1 designed with a primary pharmacodynamic endpoint of preferential mobilization of a5b1-expressing circulating tumor cells into the peripheral blood of men with bone-dominant metastases could permit evidence for the role of the a5b1pathway in mediating adhesive interactions of prostate cancer cells in the bone marrow.…”

Targeted inhibition of Snail family zinc finger transcription factors by oligonucleotide-Co(III) Schiff base conjugate

“…The resultant light pink crude material was purified by flash column chromatography over silica gel with toluene:ether:acetic acid (63:35:2) to give a pale yellow oil (1.999 g, 91%). 1 676 g, 82%). Without further purification, the diamine (1.148 g, 7.16 mmol) was dissolved in 15 mL methanol:ethanol (2:3) and slowly added via addition funnel to a 15-mL solution of 2,4-pentadione (7.4 mL, 71.8 mmol) in methanol:ethanol (2:3) with vigorous stirring at 0°C.…”

“…This crude material was recrystalized in hot toluene to give a white crystalline solid (0.984 g, 42%). 1 [Co(III)(Heptanoic Acido)(Acacen)(NH 3)2] ؉ CH3COO ؊ [Co(III)-sb]. Cobalt acetate (0.182 g, 0.732 mmol) was dissolved in 5 mL methanol and filtered whereas compound 4 (0.238 g, 0.733 mmol) was dissolved separately in 5 mL methanol.…”

“…B reast cancer is a heterogeneous disease with fatalities resulting from recurrence and metastasis to distant sites including bone, lung, liver, and brain (1). The zinc finger transcription factors Slug, Snail, and Sip1 have been implicated in tumor metastasis through the regulation of epithelial-tomesenchymal transitions (EMTs) (2)(3)(4)(5).…”