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

Cancer Res. 1989 Sep 1;49(17):4740-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Factors / biosynthesis
  • Blotting, Northern
  • Carcinoma, Squamous Cell / complications*
  • Carcinoma, Squamous Cell / metabolism
  • Colony-Stimulating Factors / biosynthesis*
  • Cytokines*
  • Granulocyte Colony-Stimulating Factor
  • Humans
  • Hypercalcemia / etiology*
  • Interleukin-1 / biosynthesis*
  • Leukocytosis / etiology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Neoplasm Proteins / biosynthesis*
  • Paraneoplastic Syndromes / etiology*
  • Parathyroid Hormone-Related Protein
  • RNA, Messenger / analysis
  • Tumor Cells, Cultured


  • Biological Factors
  • Colony-Stimulating Factors
  • Cytokines
  • Interleukin-1
  • Neoplasm Proteins
  • PTHLH protein, human
  • Parathyroid Hormone-Related Protein
  • RNA, Messenger
  • bone resorption factor
  • Granulocyte Colony-Stimulating Factor