Abstract
Outcomes for young people diagnosed with osteosarcoma hinge almost exclusively on whether they develop lung metastasis. The striking predilection that osteosarcoma shows for metastatic spread to lung suggests properties and/or lung interactions that generate tissue-specific survival and proliferation advantages. While these mechanisms remain overall poorly defined, studies have begun to describe biological elements important to metastasis. Mechanisms described to date include both cell-autonomous adaptations that allow disseminated tumor cells to survive the stressors imposed by metastasis and intercellular signaling networks that tumor cells exploit to pirate needed signals from surrounding tissues or to recruit other cells that create a more favorable niche. Evidence suggests that cell-autonomous changes are largely driven by epigenetic reprogramming of disseminated tumor cells that facilitates resistance to late apoptosis, manages endoplasmic reticulum (ER) stressors, promotes translation of complex transcripts, and activates clotting pathways. Tumor-host signaling pathways important for lung colonization drive interactions with lung epithelium, mesenchymal stem cells, and mediators of innate and adaptive immunity. In this chapter, we highlight one particular pathway that integrates cell-autonomous adaptations with lung-specific tumor-host interactions. In this mechanism, aberrant ΔNp63 expression primes tumor cells to produce IL6 and CXCL8 upon interaction with lung epithelial cells. This tumor-derived IL6 and CXCL8 then initiates autocrine, osteosarcoma-lung paracrine, and osteosarcoma-immune paracrine interactions that facilitate metastasis. Importantly, many of these pathways appear targetable with clinically feasible therapeutics. Ongoing work to better understand metastasis is driving efforts to improve outcomes by targeting the most devastating complication of this disease.
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Reinecke, J.B., Roberts, R.D. (2020). Targetable Intercellular Signaling Pathways Facilitate Lung Colonization in Osteosarcoma. In: Kleinerman, E., Gorlick, R. (eds) Current Advances in the Science of Osteosarcoma. Advances in Experimental Medicine and Biology, vol 1258. Springer, Cham. https://doi.org/10.1007/978-3-030-43085-6_7
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