Fig. 8: HIF signaling in the primary tumor drives dissemination to the bone but only modestly alters factors known to regulate bone metastasis.

a–c Quantitative PCR analysis of Pthlh transcript compared to B2m in primary tumor with deletion of Vhl, Hif1α, or Hif2α, respectively. Two-tailed Mann–Whitney test. d–f Quantitative PCR analysis of Cxcr4 transcript compared to B2m in primary tumor with deletion of Vhl, Hif1α, or Hif2α, respectively. Two-tailed Mann–Whitney test. g Summary of findings. VHL and HIF1α expression in the primary tumor drive tumor growth, and VHL expressing tumors are larger, while HIF1α-expressing tumors are smaller on average. HIF1α expression in the primary tumor also disrupts bone homeostasis, leading to decreased bone volume. This disruption of the bone inhibits tumor cell dissemination to bone, while likely promoting tumor cell dissemination and outgrowth in the lung. HIF2α drives bone dissemination but does not influence lung metastasis. As the negative regulator of HIF signaling, VHL inhibits bone metastasis but VHL expression does not alter metastatic tumor burden in the lung. Image created with BioRender.com. Graphs represent mean per group and error bars represent s.e.m. n = 20 Vhl^f/f PyMT⁺ mice, n = 18 Vhl^−/− PyMT⁺ mice, n = 19 Hif1α^f/f PyMT⁺ mice, n = 21 Hif1α^−/− PyMT⁺ mice, n = 19 Hif2α^f/f PyMT⁺ mice, n = 18 Hif2α^−/− PyMT⁺ mice.