Abstract 56: CXCL5 is a master regulator of the dormancy switch to activate metastatic colonization of dormant breast cancer cells during bone metastasis
Authors: Ricardo Romero-Moreno, Thomas Coughlin, Kimberly Curtis, Shourik Dutta, Glen Niebur, Laurie E. Littlepage
Journal: Cancer Research (2018)

Abstract Bone is one of the most common and most dangerous sites for metastatic tumor growth across cancer types, including breast cancer. At death, roughly 73% of women with breast cancer have bone metastasis, most often growing in highly vascularized bones. These metastases are detrimental to the patient's quality of life, causing hypercalcemia, acid/base imbalance, aberrant hematopoiesis, immune response, and osteolysis (bone loss) resulting in severe pain and immobility. Current treatment options for patients with metastatic bone cancer include chemotherapy, palliative radiation, and surgical resection. However, bone metastasis is not considered curable with current therapies. Circulating tumor cells sometimes become arrested in blood vessels or within tissue, remaining in a quiescent state ("dormancy") until the right conditions induce the cancer cells to grow and thrive in the metastatic site ("colonization"). Switching cancer cells from dormancy to colonization is rate-limiting for bone metastasis, sometimes taking decades to induce metastatic tumor growth. With few experimental models available to study this last step of metastasis, the switch from cancer dormancy to colonization, or dormancy switch, has become one of the greatest challenges in cancer treatment and cancer research. Most of the experimental models that are used focus on either in vitro culture systems, lacking the heterogeneity of an intact bone, or in vivo animal models that are not amenable to higher-throughput experimentation. To model dormancy, we developed an ex vivo co-culture system of mouse bones and cancer cells. Using our culture system, we then identified distinct culture conditions for tumor cell dormancy and colonization in bone. In fact, conditioned media from our dormancy culture conditions induced dormancy of cancer cells. Profiling of a panel of cytokines, chemokines, and growth factors identified the chemokine CXCL5 as a candidate to induce the switch from dormancy to colonization. Interestingly, bones from mice that harbored tumor cells before collection support a higher cancer cell proliferation rate in co-culture and secrete more CXCL5 than bones from healthy mice. This suggests that bones primed with cancer cells form a niche that actively supports the proliferation of metastatic cells and is inducible by CXCL5. In culture, devitalized bones and conditioned media from devitalized cultures support cancer cell proliferation, which suggests that the bone and/or marrow express an inhibitor of cancer cell proliferation. Additional studies using CXCL5 recombinant protein further suggest that CXCL5 is sufficient to overcome breast cancer dormancy and promote proliferation in metastatic breast cancer. Together, this study supports the importance of the communication between the bone microenvironment and cancer cells to further promote metastatic colonization. Citation Format: Ricardo Romero-Moreno, Thomas Coughlin, Kimberly Curtis, Shourik Dutta, Glen Niebur, Laurie E. Littlepage. CXCL5 is a master regulator of the dormancy switch to activate metastatic colonization of dormant breast cancer cells during bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 56.