Evidence that tumor necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumor in nude mice.

Abstract

Recently, we have established a human squamous cell carcinoma of the maxilla (called MH-85) associated with hypercalcemia, leukocytosis, and cachexia in culture. MH-85 tumor cells caused the same paraneoplastic syndromes in tumor-bearing nude mice. We found that there was a sixfold increase in splenic size in MH-85 tumor-bearing mice. This increase paralleled tumor growth and was reversed by surgical removal of the tumor. Splenectomy in nude mice 1 wk before or 6 wk after tumor inoculation resulted in a decrease in tumor growth, and impairment of hypercalcemia, leukocytosis, and cachexia. In MH-85 tumor-bearing animals that had been pretreated by splenectomy, intravenous injection of fresh normal spleen cells caused an immediate reversal of leukocytosis, hypercalcemia, and cachexia. Since the presence of cachexia in both the patient and the mice carrying the tumor suggested tumor necrosis factor (TNF) may be overproduced, we injected polyclonal neutralizing antibodies raised against murine TNF into tumor-bearing mice. There was a rapid and reproducible decrease in blood ionized calcium, accompanied by suppression of osteoclast activity. No changes in blood ionized calcium were seen in mice injected with normal immune sera. In addition, there was an increase in body weight and decrease in white cell count. Plasma immunoreactive TNF was increased almost fourfold in tumor-bearing nude mice compared with control nude mice. Although TNF activity was undetectable in MH-85 culture supernatants, cells of the macrophage lineage, including spleen cells, released increased amounts of TNF when cultured with MH-85 tumor-conditioned media. These results suggest that splenic cytokines such as TNF may influence the development of the paraneoplastic syndromes of hypercalcemia, leukocytosis, and cachexia in these animals, as well as tumor growth. They also show that paraneoplastic syndromes may be due to factors produced by normal host cells stimulated by the presence of the tumor. (J. Clin. Invest. 1991. 87:977-985.)

Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia

“…Lung carcinoma has been known to have a predilection for spreading to bone. 10 Recent studies suggest that PTH-rP plays a critical role in tumor invasion and distant metastasis 22,23 and facilitates dissemination of breast and prostate carcinoma to bone. 6,24 -26 These previous observations led us to determine the relation between serum levels of PTH-rP and the development of bone metastases in lung carcinoma patients with TIH.…”

“…We specifically examined the relation between serum levels of PTH-rP and bone metastases because lung carcinoma has a strong predilection for spreading to bone 10 and PTH-rP is implicated in bone metastases in malignancies such as breast carcinoma. 5 Our data confirm that PTH-rP is elevated in lung carcinoma patients with TIH.…”

Tumour inoculation site-dependent induction of cachexia in mice bearing colon 26 carcinoma

“…Cachexia is known to be caused by mediators produced by tumours or by the host as a result of tumour-host interaction. Previously, various factors have been proposed as cachexia mediators, such as tumour necrosis factor alpha (TNF-α) (Oliff et al, 1987;Tracey et al, 1988;Stovroff et al, 1988;Yoneda et al, 1991), interferon gamma (IFN-γ) (Matthys et al, 1991a(Matthys et al, , 1991b, interleukin (IL)-1α (Moldawer et al, 1987;Gelin et al, 1991), leukaemia inhibitory factor (LIF) (Mori et al, 1991) and IL-6 (Yoneda et al, 1993;Tamura et al, 1995). Fujimoto-Ouchi et al (1995) and Strassmann et al (1992a) reported that anti-IL-6 antibody suppressed the progressive body weight loss and other disorders associated with cachexia in mice bearing colon 26.…”

Regulation of Granulocyte Colony‐stimulating Factor and Parathyroid Hormonerelated Protein Production in Lung Carcinoma Cell Line OKa‐C‐1

“…8,34) However, it has been reported that several inflammatory cytokines, which are produced by host immune cells or tumor cells themselves, could influence the production of G-CSF and PTHrP during the course of malignant disease. 28) Indeed, Rizzoli et al have shown that PMA, IL-6 and TNF-α induced an increase in PTHrP production by a human lung squamous cell carcinoma line, which was associated with elevated levels of PTHrP mRNA.…”

“…1,2,28,29) The production of G-CSF and PTHrP by cancer cells is thought to be responsible for these paraneoplastic syndromes. However, the mechanism of simultaneous and unrestricted production of G-CSF and PTHrP by cancer cells is not well delineated.…”