The role of interleukin-6 in the induction of hypercalcemia in renal cell carcinoma transplanted into nude mice.
Hypercalcemia is a well known complication of renal cell carcinoma (RCC). As RCCs can produce IL-6, and IL-6 may stimulate bone resorption and cause mild hypercalcemia, we examined whether IL-6 is involved in renal cancer-associated hypercalcemia in vivo. Three human renal cell carcinoma tumor lines (RC-8, RC-9, and NC-65) growing in nude mice were studied. Tumors were implanted s.c., and parameters of bone metabolism and serum human IL-6 levels were determined in relation to tumor volume (TV). All three tumor lines secreted human IL-6, although in different quantities. The maximum level of IL-6 in RC-8 was 434 pg/ml (TV, 200 mm3), that in RC-9 was 81 pg/ml (TV, 1800 mm3), and that in NC-65 was 2368 pg/ml (TV, 1800 mm3). Hypercalcemia developed in RC-8 and RC-9 tumor-bearing animals, but not in NC-65-bearing animals. The hypercalcemia in both RC-8 and RC-9 tumor lines was associated with elevated levels of PTH-related peptide (PTHrP) and loss of trabecular bone volume. Serum calcium and phosphate concentrations showed an almost linear relationship with plasma PTHrP independently of the tumor line and serum IL-6 levels. No hypercalcemia occurred in the NC-65 animals, which had the highest levels of IL-6, but no detectable plasma PTHrP and PTHrP messenger RNA expression in the tumor. Administration of neutralizing antibodies to IL-6 to RC-8 animals normalized serum calcium concentrations and PTHrP values and induced a significant inhibition of tumor growth. No such effect on tumor growth of anti-IL-6 was seen in the other two tumor lines. The normalization of serum calcium in RC-8 mice is most likely attributed to the growth-inhibiting effect of anti-IL-6 on RC-8 tumor. We conclude that IL-6 secreted by RCC does not contribute directly to hypercalcemia, but may enhance hypercalcemia by stimulating the tumor growth of a subpopulation of PTHrP-secreting carcinomas.
Weissglas
M G
MG
Department of Urology, University Hospital Leiden, The Netherlands.
Schamhart
D H
DH
Löwik
C W
CW
Papapoulos
S E
SE
Theuns
H M
HM
Kurth
K H
KH
D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D002118:Calcium / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000150:complications* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology*; D007116:Immunization, Passive; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007680:Kidney Neoplasms / Q000150:complications* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D044162:Parathyroid Hormone-Related Protein; D010710:Phosphates / Q000097:blood; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D010710:Phosphates; D011506:Proteins; D012333:RNA, Messenger; D002118:Calcium