Osteoclasts are required for bone tumors to grow and destroy bone

Abstract

It has been hypothesized that bone resorption during tumor osteolysis is performed by osteoclasts. Data supporting this hypothesis have been provided from analysis of human biopsy specimens obtained from sites of tumor osteolysis, as well as from experimentation with in vivo animal models. Experiments in this report take this concept one step further by testing the hypothesis that osteoclasts are required for bone tumors to grow and destroy bone. To test this hypothesis, the influence of an osteolytic sarcoma tumor, NCTC clone 2472 (2472), on bone was studied in animals that are osteoclast deficient (microphthalmic, strain B6C3Fe-a/a-Mitf(mi)) but whose osteoclast deficiency can be reversed following bone marrow transplantation. Femora of these mice and unaffected wild-type siblings were injected with 10(5) 2472 cells, and after 14 days the femora were analyzed by radiographic and histomorphometric analysis. Macroscopic tumor, tumor-induced osteolysis, and increased osteoclast number were noted in femora of normal mice but not in femora of osteoclast-deficient mice (p < 0.001). Bone marrow transplantation converted osteoclast-deficient mice to mice with femora that contained osteoclasts in 4 weeks. Femora of these mice were then injected with 10(5) 2472 tumor cells; after 14 days, in contrast to the findings in the original osteoclast-deficient mice, macroscopic tumor was present, tumor-induced osteolysis was noted on roentgenograms, and osteoclast number was increased when tumor-bearing limbs were compared with sham-injected limbs (p < 0.001). These data prove the hypothesis that osteoclasts are required for 2472 tumor-induced osteolysis, and they introduce the exciting possibility that osteoclasts are also required for tumors to grow in bone.

Cellular mechanisms of bone resorption in breast carcinoma

“…This finding is of interest with regard to the pathogenesis of tumour osteolysis in breast cancer as, in addition to an increase in osteoclast number, a prominent macrophage infiltrate is commonly found in metastatic breast carcinomas (Bugelski et al, 1987;Van Ravenswaay Claasen et al, 1992). Moreover, osteoclasts are required for growth of breast cancer metastases in bone and tumour osteolysis involves recruitment of osteoclast precursors and activation of mature osteoclasts (Clohisy et al, 1996a(Clohisy et al, , 1996bClohisy and Ramnaraine, 1998).In this study, our aim has been to analyse the cellular mechanisms of bone resorption in breast cancer. As TAMs in metastases of breast cancer are derived from circulating monocytes (Mantovani et al, 1992), we have sought to determine whether the Summary The cellular mechanisms that account for the increase in osteoclast numbers and bone resorption in skeletal breast cancer metastasis are unclear.…”

“…This finding is of interest with regard to the pathogenesis of tumour osteolysis in breast cancer as, in addition to an increase in osteoclast number, a prominent macrophage infiltrate is commonly found in metastatic breast carcinomas (Bugelski et al, 1987;Van Ravenswaay Claasen et al, 1992). Moreover, osteoclasts are required for growth of breast cancer metastases in bone and tumour osteolysis involves recruitment of osteoclast precursors and activation of mature osteoclasts (Clohisy et al, 1996a(Clohisy et al, , 1996bClohisy and Ramnaraine, 1998).…”

Animal Models of Cancer Pain

“…101,104 Because osteoclast activity is crucial for bone resorption, 28,101,104 if osteoclast activity causing bone destruction could be inhibited, cancer-induced pain might be relieved. 30,60,69,70,164 On the basis of this concept, several investigators demonstrated that they could administer the novel analgesic osteoprotegerin ligand and successfully treat cancer pain in male C3H/HeJ mice. 69 Osteoprotegerin ligand is a member of the tumor necrosis factor family and blocks osteoclast activity that causes cancer-induced bone destruction.…”

Advances in understanding bone cancer pain

“…Upon activation, osteoclasts have been shown to cause cancer-induced osteolysis in bone [Clohisy and Ramnaraine, 1998]. Novel experimental models allow osteolytic bone destruction to be correlated to pain behaviors, neurochemical changes, and cellular reorganization of the spinal cord [Hukkanen et al, 1992;Honore et al, 2002;Sevcik et al, 2004].…”