Abstract
Therapies that target cancer cells may have unexpected effects on the tumor microenvironment that affects therapy outcomes or render therapy resistance. Prostate cancer (PCa) bone metastasis is uniquely associated with osteoblastic bone lesions and treatment with cabozantinib, a VEGFR-2 and MET inhibitor, leads to a reduction in number and/or intensity of lesions on bone scans. However, resistance to cabozantinib therapy inevitably occurs. We examined the effect of cabozantinib on osteoblast differentiation and secretion in the context of therapy resistance. We showed that primary mouse osteoblasts express VEGFR2 and MET and cabozantinib treatment decreased osteoblast proliferation but enhanced their differentiation. A genome-wide analysis of transcriptional responses of osteoblasts to cabozantinib identified a set of genes accounting for inhibition of proliferation and stimulation of differentiation, and a spectrum of secreted proteins induced by cabozantinib, including pappalysin, IGFBP2, WNT 16, and DKK1. We determined that these proteins were upregulated in the conditioned medium of cabozantinib-treated osteoblasts (CBZ-CM) compared to control CM. Treatment of C4-2B4 or PC3-mm2 PCa cells with CBZ-CM increased the anchorage-independent growth and migration of these PCa cells compared to cells treated with control CM. These results suggest that the effect of cabozantinib on the tumor microenvironment may increase tumor cell survival and cause therapy resistance.
Highlights
Many targeted therapies aim to modulate specific cancer signaling pathways
To examine whether osteoblasts could be a target of cabozantinib, we examined whether MET and VEGFR2 are expressed in osteoblasts
To prepare differentiated Primary mouse osteoblasts (PMOs), the D0 osteoblasts were further cultured in differentiation medium for 24 days (D24 osteoblasts), which resulted in an increase in the expression of osteocalcin, a marker of osteoblast differentiation, compared to D0 osteoblasts (Figure 1A, left panel)
Summary
Many targeted therapies aim to modulate specific cancer signaling pathways. While these therapies are intended for targets that are expressed in cancer cells, these targets frequently are present in stromal cells in the tumor microenvironment. Cabozantinib was used to treat prostate cancer (PCa) bone metastasis in phase II and III clinical trials [2, 3]. While the results of phase II clinical trials of cabozantinib on PCa bone metastasis were promising, the phase III clinical trial fails to show improvement in patients’ survival [3]. Cabozantinib was shown to improve outcomes of other cancers and has been approved for the treatment of advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy [5]
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