Abstract
Bone is one of the most common sites for metastasis across cancers. Cancer cells that travel through the vasculature and invade new tissues can remain in a non-proliferative dormant state for years before colonizing the metastatic site. Switching from dormancy to colonization is the rate-limiting step of bone metastasis. Here we develop an ex vivo co-culture method to grow cancer cells in mouse bones to assess cancer cell proliferation using healthy or cancer-primed bones. Profiling soluble factors from conditioned media identifies the chemokine CXCL5 as a candidate to induce metastatic colonization. Additional studies using CXCL5 recombinant protein suggest that CXCL5 is sufficient to promote breast cancer cell proliferation and colonization in bone, while inhibition of its receptor CXCR2 with an antagonist blocks proliferation of metastatic cancer cells. This study suggests that CXCL5 and CXCR2 inhibitors may have efficacy in treating metastatic bone tumors dependent on the CXCL5/CXCR2 axis.
Highlights
Bone is one of the most common sites for metastasis across cancers
We developed an ex vivo culture system in which cancer cells survive, remain metabolically active, and are supported by bone marrow to identify factors, including C-X-C chemokine motif ligand 5 (CXCL5), that regulate the colonization of breast cancer cells metastasized to bone
To measure bone viability in culture, we quantified the metabolic activity of increasing numbers of cultured mouse long bones per well (Fig. 1b, Supplementary Fig. 1) and found that bones remained metabolically active after 4 weeks in culture
Summary
Bone is one of the most common sites for metastasis across cancers. Cancer cells that travel through the vasculature and invade new tissues can remain in a non-proliferative dormant state for years before colonizing the metastatic site. Additional studies using CXCL5 recombinant protein suggest that CXCL5 is sufficient to promote breast cancer cell proliferation and colonization in bone, while inhibition of its receptor CXCR2 with an antagonist blocks proliferation of metastatic cancer cells. In breast cancer patients with metastatic disease, bone is the most common site of metastasis and the most common site of first distant relapse, with roughly half (48%) of breast cancer patients developing bone metastases after systemic treatment[1,2,3]. Roughly 73% of women with breast cancer[4,5] have bone metastasis, mostly growing in highly vascularized bones[6]. While breast cancer patients with metastases exclusively in bone have higher survival rates than patients with metastases in multiple tissues including bone, patients with the worst prognosis have metastasis in multiple tissue locations[8,9]. Current treatments for patients with metastatic bone cancer include combinations of chemotherapy, palliative radiation, antiresorptive agents such as bisphosphonates, antibodies that inhibit osteoclastogenesis, and rarely surgical resection[15,16,17]
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