Abstract
Bone metastasis of colorectal cancer (CRC) cells leads to osteolysis. Aberrant activation of osteoclasts is responsible for bone resorption in tumor. In general, bone marrow-derived monocytes (BMMs) differentiate into osteoclasts, however, how CRC cells interact with BMMs and how to regulate the differentiation is elusive. We here report that CRC cells promote bone resorption in bone metastasis. Transcriptomic profiling revealed CCL3 up-regulated in MC-38 conditional medium treated BMMs. Further investigation demonstrated that CCL3 produced by BMMs facilitated cell infusion and thus promoted the osteoclastogenesis. In addition, CRC cells derived EGF stimulated the production of CCL3 in BMMs through activation of ERK/CREB pathway. Blockage of EGF or CCL3 can efficiently attenuate the osteolysis in bone metastasis of CRC.
Highlights
Bone metastasis can occur in several cancers, including breast, lung, bladder, colorectal cancers (CRCs) [1,2,3]
Clinical and experimental evidence indicates CRC can cause osteolytic lesions in bone metastasis, it remains elusive how osteoclastogenesis is activated in CRC and how CRC cells interact with osteoclasts or the precursors
We indicate the importance of CCL3 in osteoclastogenesis in bone metastasis of CRC
Summary
Bone metastasis can occur in several cancers, including breast, lung, bladder, colorectal cancers (CRCs) [1,2,3]. The incidence is relatively low in CRC, CRC patients with bone metastasis present with a lower average age and are frequently associated with much poorer prognosis [2,4]. Numerous evidences showed the imbalance of functional cells within the bone, i.e. osteoblasts and osteoclasts, is responsible for the development of bone lesions, of which aberrant osteoclast activity leads to lytic bone metastasis [5,6,7]. Little is known about the effect of CRC cells on BMMs. Notably, bone marrow could be the isolated metastatic site in CRC [9,10], implying the interaction between CRC cells and BMMs may be important in bone metastasis of CRC
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