Paraneoplastic syndrome of hypercalcemia and leukocytosis caused by squamous carcinoma cells (T3M-1) producing parathyroid hormone-related protein, interleukin 1 alpha, and granulocyte colony-stimulating factor.
Previously we reported that a clonal squamous cell carcinoma cell line (T3M-1) derived from a lower jaw cancer of a patient with marked leukocytosis and hypercalcemia produced factors containing a potent bone-resorbing activity (BRA) (Mr 15,000-20,000) and a colony-stimulating activity. To elucidate the pathogenesis of this humoral hypercalcemia, BRA and colony-stimulating activity in both the conditioned medium and cells were characterized. The conditioned medium, when eluted at neutral pH, contained colony-stimulating activity and thymocyte proliferation-stimulating activity, the latter of which comigrated with BRA. Upon elution with acetic acid (pH 2.0), the conditioned medium contained no interleukin 1-like activity but potent parathyroid hormone-like activity, which comigrated with BRA. Northern blot hydridization analysis revealed that T3M-1 cells produced constitutively mRNA for parathyroid hormone-related protein and granulocyte colony-stimulating factor. Furthermore, primer extension analysis revealed that the cells also produced mRNA for interleukin 1 alpha (IL-1 alpha). Since parathyroid hormone-related protein and IL-1 alpha (osteoclast-activating factor) synergistically increase the concentration of serum calcium, and since IL-1 alpha (hemopoietin 1) potentiates granulocyte colony-stimulating factor-induced granulocytopoiesis, we speculate that parathyroid hormone-related protein, granulocyte colony-stimulating factor, and IL-1 alpha are synergistically involved in a paraneoplastic syndrome of hypercalcemia and leukocytosis, at least in some patients with solid tumors.
Sato
K
K
Institute of Clinical Endocrinology, Tokyo Women's Medical College, Japan.
Fujii
Y
Y
Kakiuchi
T
T
Kasono
K
K
Imamura
H
H
Kondo
Y
Y
Mano
H
H
Okabe
T
T
Asano
S
S
Takaku
F
F
D000818:Animals; D001685:Biological Factors / Q000096:biosynthesis; D015152:Blotting, Northern; D002294:Carcinoma, Squamous Cell / Q000150:complications* / Q000378:metabolism; D003115:Colony-Stimulating Factors / Q000096:biosynthesis*; D016207:Cytokines; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology*; D007375:Interleukin-1 / Q000096:biosynthesis*; D007964:Leukocytosis / Q000209:etiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010257:Paraneoplastic Syndromes / Q000209:etiology*; D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured
D001685:Biological Factors; D003115:Colony-Stimulating Factors; D016207:Cytokines; D007375:Interleukin-1; D009363:Neoplasm Proteins; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger; C025940:bone resorption factor; D016179:Granulocyte Colony-Stimulating Factor