Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

Abstract

Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.

Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia

“…Indeed, examining this organ crosstalk within cachexia may provide important clues to teasing out the mechanisms that drive this morose disease. Our group and others have demonstrated that cancer-induced cachexia does not solely affect skeletal muscle, but that heart, fat, and bone are also impaired (23,26,28,50). In particular, recent observations have implicated that abnormal muscle-bone crosstalk may play a significant role in cancer cachexia.…”

“…In particular, recent observations have implicated that abnormal muscle-bone crosstalk may play a significant role in cancer cachexia. For example, observations generated in several mouse models of CRC, including C26, HT-29, and Apc min/+ , revealed differential bone loss, despite consistent loss of skeletal muscle mass (28). Interestingly, cancellous bone in the femurs of C26 tumor hosts was generally maintained, whereas in the present study, the use of C26 tumor cells to induce LMs was sufficient to drive both skeletal muscle and bone loss (Figure 9), further indicating an exacerbation in bone phenotype with LMs.…”

“…CRC (23,(26)(27)(28). Interestingly, the traditional C26 allograft model does not present with significant bone disruption (28). Therefore, we sought to examine whether the mC26 model drove bone loss in addition to skeletal muscle wasting.…”

Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia

“…Although no functional measurements were performed on the bones from ES-2 hosts, our previous evidence suggests that bone content generally correlates with the overall bone strength in cancer cachexia. 67 Although the molecular mechanism(s) responsible for bone depletion in association with the occurrence of OC are not known, high levels of IL-6, as shown in the animals bearing the ES-2 OC, have been previously reported in association not only with the development of paraneoplastic complications, such as cachexia, leucocytosis, and thrombocytosis, but also with the occurrence of hypercalcaemia, a condition responsible for severe loss of bone mass, 68 or juvenile idiopathic arthritis, a systemic inflammatory condition characterized by clinical features that include stunted growth and skeletal abnormalities. 69,70 In this regard, elevated IL-6 seems to play a relevant role by primarily affecting bone turnover, along with increased bone resorption and reduced bone formation.…”

“…69,70 In this regard, elevated IL-6 seems to play a relevant role by primarily affecting bone turnover, along with increased bone resorption and reduced bone formation. 71 Unlike our previous reports describing the occurrence of bone loss following development of colorectal tumours or after prolonged administration of chemotherapy, 48,67 bone tissue is not generally investigated in the experimental models utilized for the study of HGS-OCs. In the clinical setting, OC is not frequently associated with enhanced bone fractures per se or described as a risk factor for the development of osteoporosis, although elevated bone turnover markers were detected in women undergoing risk-reducing salpingooophorectomy to decrease the risk for breast cancer and OC.…”