Increased fibroblast growth factor-like autoantibodies in serum from a subset of patients with cancer-associated hypercalcemia.
Basic fibroblast growth factor (bFGF) is a potent tumor angiogenesis factor which lacks an amino-terminal signal sequence and does not normally circulate in serum from normal subjects. Naturally-occurring autoantibodies which mimicked basic fibroblast growth factor were described in serum from patients with multiple endocrine neoplasia type 1 prolactinoma or sporadic growth-hormone-secreting adenoma associated with increased bFGF. Since bFGF was increased in serum from a variety of cancers, we used endothelial cell proliferation assay(s) to test for bioactivity in the IgG fraction of serum from 56 patients with cancer-associated hypercalcemia, and normal or control subjects. We now report increased IgG-like endothelial cell activity in serum from a hyper prolactinemic subset (4/19 breast cancer; 1/14 renal cancer; 0/23 lung cancer) of cancer-associated hypercalcemic subjects. Highest activity was found in serum from three breast cancer patients who suffered spinal cord compression/metastases. The activity had properties of antiidiotype bFGF antibodies including reaction with anti-human IgG antibodies, and complete neutralization by rabbit antibodies to intact bFGF. The activity in endothelial cells persisted after storage at 0-4 C for 5 yrs; and [prepared by SDS-PAGE and immunoblotting with anti-human IgG] had apparent mol wt corresponding to the heavy chains of IgG. Serum IgG-like activity from 5 of 5 breast cancer patients and 2 of 2 prostate cancer subjects tested [prepared by anti-bFGF antibody, protein-A immunoaffinity, and hydroxyapatite (HA) chromatography] yielded peak HA-adsorbed activity that eluted with 0.4 M sodium phosphate, and was neutralized 70% by antibodies to intact bFGF. Cancer sera mean peak specific activity (12.0 ng-eq bFGF/ug protein) (n = 7) significantly exceeded (P < 0.001) normal sera mean peak specific activity (0.46 ng-eq bFGF/ug protein) (n = 6) in the 0.4 M sodium phosphate eluate fraction from hydroxyapatite columns. These results imply that long-lasting, bioactive FGF-like autoantibodies may arise spontaneously (and contribute to pathophysiology) in subsets of cancer patients with osseous metastases.
Zimering
Mark B
MB
Department of Veterans Affairs, Medical Service, New Jersey Health Care System (MBZ), 07939, Lyons, NJ 07939, USA. mark.zimering@med.va.gov
Thakker-Varia
Smita
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000494:pharmacology; D001859:Bone Neoplasms / Q000097:blood* / Q000150:complications / Q000556:secondary; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D006934:Hypercalcemia / Q000097:blood* / Q000209:etiology / Q000473:pathology; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008875:Middle Aged; D009500:Neutralization Tests; D011388:Prolactin / Q000097:blood; D011817:Rabbits; D014407:Tumor Cells, Cultured
D001323:Autoantibodies; D007074:Immunoglobulin G; D016222:Fibroblast Growth Factor 2; D011388:Prolactin