title: Relationship of plasma bone cytokines with hypercalcemia in cancer patients.
abstract: The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. This syndrome appears to be a consequence of the tumor production of humoral factors, mainly parathyroid hormone related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy have features suggesting that factors other than PTHrP might play a role in this syndrome. We performed a case-control study in cancer patients with and without hypercalcemia. A total of 105 patients with a variety of tumors, 60 of them with hypercalcemia (corrected serum calcium over 2.6 mmol/l), and 45 without hypercalcemia. In a previous study, we demonstrated that plasma PTHrP was highly associated with hypercalcemia in these patients. In the present study, we measured the plasma levels of various bone cytokines: interleukin-1beta (IL-1beta), interleukin-6 (IL-6), transforming growth factor (TGF) alpha, and tumor necrosis factor (TNF) alpha, in these cancer patients. We also determined C-terminal type I procollagen (PICP) and C-terminal telopeptide of type I collagen (ICTP), bone formation and bone resorption markers, respectively, in serum in these patients. We found that these osteolytic cytokines do not increase in plasma by the presence of hypercalcemia. In fact, using a logistic regression analysis, a significant (P<0.02) association was found between the low plasma levels of IL-1beta and TGFalpha and hypercalcemia, independent of plasma PTHrP and the presence of bone metastasis, in these patients. No significant association between the plasma levels of IL-6 or TNFalpha and hypercalcemia was found in these cancer patients. Serum ICTP correlated (r=0.35; P=0.008) with hypercalcemia in these patients, but none of the cytokines studied in plasma correlated with either ICTP or PICP in these hypercalcemic patients. Our data indicate that the circulating levels of several bone cytokines are not enhanced by PTHrP in hypercalcemic cancer patients. The mechanism responsible for the association between the low plasma levels of some of these cytokines and hypercalcemia in these patients remains obscure. However, this finding does not rule out the possible local bone effects of these cytokines, contributing to hypercalcemia in cancer patients.
authors.affiliation: Department of Nephrology, Hospital de la Princesa, Madrid, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Motellón
authors.forename: F J
authors.initials: FJ
authors.lastname: Jiménez
authors.forename: F
authors.initials: F
authors.lastname: de Miguel
authors.forename: M J
authors.initials: MJ
authors.lastname: Jaras
authors.forename: A
authors.initials: A
authors.lastname: Díaz
authors.forename: J
authors.initials: J
authors.lastname: Hurtado
authors.forename: P
authors.initials: P
authors.lastname: Esbrit
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D001846:Bone Development; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism*; D003094:Collagen / Q000097:blood; D024042:Collagen Type I; D016207:Cytokines / Q000097:blood*; D006801:Humans; D006934:Hypercalcemia / Q000097:blood* / Q000209:etiology*; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000097:blood; D010455:Peptides / Q000097:blood; D011347:Procollagen / Q000097:blood; D011506:Proteins / Q000032:analysis; D016211:Transforming Growth Factor alpha / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D010455:Peptides; D011347:Procollagen; D011506:Proteins; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; C052929:collagen type I trimeric cross-linked peptide; C042813:procollagen type I carboxy terminal peptide; D003094:Collagen