Parathyroid hormone–related protein (PTHrP) as a causative factor of cancer‐associated wasting: Possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts

Abstract

Nude rats bearing the LC-6-JCK human lung cancer xenograft displayed cancer-associated wasting syndrome in addition to humoral hypercalcemia of malignancy. In these rats, not only PTHrP but also several other human proinflammatory cytokines, such as IL-6, leukemia-inducing factor, IL-8, IL-5 and IL-11, were secreted to the bloodstream. Proinflammatory cytokines induce acute-phase reactions, as evidenced by a decrease of serum albumin and an increase in a1-acid glycoprotein. Tumor resection abolished the production of proinflammatory cytokines and improved acute-phase reactions, whereas anti-PTHrP antibody affected neither proinflammatory cytokine production nor acutephase reactions. Nevertheless, tumor resection and administration of anti-PTHrP antibody similarly and markedly attenuated not only hypercalcemia but also loss of fat, muscle and body weight. Body weight gain by anti-PTHrP antibody was associated with increased food consumption; increased body weight from antiPTHrP antibody was observed when animals were freely fed but not when they were given the same feeding as those that received only vehicle. Furthermore, nude rats bearing LC-6-JCK showed reduced locomotor activity, less eating and drinking and low blood phosphorus; and anti-PTHrP antibody restored them. Although alendronate, a bisphosphonate drug, decreased blood calcium, it affected neither locomotor activity nor serum phosphorus level. These results indicate that PTHrP represses physical activity and energy metabolism independently of hypercalcemia and proinflammatory cytokine actions and that deregulation of such physiologic activities and functions by PTHrP is at least in part involved in PTHrP-induced wasting syndrome. ' 2005 Wiley-Liss, Inc.Key words: parathyroid hormone-related protein; wasting; proinflammatory cytokine; acute-phase reaction; locomotor activity Cancer-associated wasting (cancer wasting) is a complex disease often associated with anorexia and cachexia and characterized by several metabolic and behavioral abnormalities, such as early satiety, weakness, fatigue, depression and weight loss. Cancer wasting occurs in about 10% of advanced cases of malignancy. It correlates with poor prognosis irrespective of tumor mass or tumor metastases 1 and affects the susceptibility to and tolerability of chemotherapy.2 Furthermore, cancer wasting is not easily resolved by forced caloric intake.3 Several factors are thought to be involved in cancer wasting. TNF-a, IL-1b, IL-6, LIF and IFN-c have been demonstrated to cause cachectic symptoms in animal models. 4 Activin, a member of the TGF-b gene family, was found to induce cachectic symptoms in mice.5 PIF, a sulfated glycoprotein that induces protein catabolism in isolated muscle cells, has been detected in serum samples from cachectic mice and from cancer patients.1 LMF, a homologue of the plasma Zn-a2 glycoprotein which induces lipid mobilization and catabolism in rats, has been isolated from the urine of cancer patients. 6 Nevertheless, the etiology of cancer cachexia is still not well...

Novel models of cancer-related anemia in mice inoculated with IL-6-producing tumor cells

“…Furthermore, Nieken et al re-ported that administration of recombinant human IL-6 as immunotherapy caused anemia in cancer patients (10). In the present study, we demonstrated that hemoglobin levels decreased in animal models bearing IL-6-producing tumor tissues such as LC-06-JCK human lung (12) and colon26 clone 5 murine colon cancers (4) and, furthermore, that a rat anti-IL-6 receptor antibody prevented the induction of cancerrelated anemia in the LC-06-JCK model. These results suggest that IL-6 could be a mediator of cancer-related anemia.…”

“…We measured the hemoglobin levels in nude rats bearing human lung cancer LC-06-JCK and human pancreatic cancer PAN-07-JCK, both of which have been previously reported to produce PTHrP and to cause cachexia with wasting in nude rats (12). Hemoglobin levels and red blood cell count were reduced in nude rats bearing LC-06-JCK but not in nude rats bearing PAN-07-JCK (Table 1).…”

“…The humanized anti-PHTrP monoclonal antibody raised against the N-terminal 34 amino acids of human PTHrP was intravenously administrated at 3 mg/kg in the LC-06-JCK and PAN-07-JCK models, as previously reported (12).…”

Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice

“…These include the soluble decoy receptor for RANKL, osteoprotegerin (OPG), anti-PTHrP antibodies and bisphosphonates. A single injection of anti-PTHrP antibodies reduced calcium and cAMP/creatinine levels near baseline levels within hours after administration in a mouse xenograft model of HHM (Kukreja et al, 1988) and humanised anti-PTHrP antibodies had a similar efficacy in a nude rat xenograft model of HHM (Sato et al, 2003;Onuma et al, 2005). One treatment with OPG reduced plasma calcium concentrations to baseline within 24 -48 h in a mouse xenograft model of HHM (Morony et al, 1999).…”

“…One treatment with OPG reduced plasma calcium concentrations to baseline within 24 -48 h in a mouse xenograft model of HHM (Morony et al, 1999). In the above models of HHM, treatment with the bisphosphonates, pamidronate, zoledronic acid and alendronate were unable to return serum calcium concentrations to baseline (Morony et al, 1999;Onuma et al, 2005).…”