Increased production of tumor necrosis factor by normal immune cells in a model of the humoral hypercalcemia of malignancy

M. Sabatini, A. J. Yates, I. R. Garrett, J. Chavez, J. F. Dunn, Lynda Bonewald, G. R. Mundy

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The rat Leydig cell tumor is a well characterized model of the humoral hypercalcemia of malignancy. The studies reported here were provoked by the observation that tumor-bearing rats become extremely cachectic and develop hypertriglyceridemia as they become hypercalcemic. Since the bone resorbing cytokine tumor necrosis factor (TNF)/cachectin is associated with cachexia and hypertriglyceridemia, we examined hypercalcemic tumor-bearing rats for evidence of increased TNF production using a TNF radioimmunoassay. We found that immunoreactive TNF was increased in the plasma of tumor-bearing rats. The increase in plasma TNF was comparable to that previously shown in hypercalcemic nude mice bearing Chinese hamster ovarian cell tumors transfected with the human TNF gene. There was no detectable TNF activity in tumor culture media which suggested that the tumor itself was not the source of excess TNF production. However, we found that tumor cell conditioned media enhanced the production of TNF activity by normal macrophages in vitro, indicating that increased TNF production in vivo may result from a tumor factor(s) which stimulates TNF production by normal immune cells. When TNF was added together with tumor products to organ cultures of fetal rat long bones, osteoclastic bone resorption was potentiated. These data are consistent with the concept that in this model of the humoral hypercalcemia of malignancy, increased TNF production by normal immune cells is increased, has systemic effects as suggested by cachexia and hypertriglyceridemia, and may work in concert with factors produced directly by tumor cells to overwhelm normal calcium homeostasis.

Original languageEnglish (US)
Pages (from-to)676-682
Number of pages7
JournalLaboratory Investigation
Volume63
Issue number5
StatePublished - 1990
Externally publishedYes

Fingerprint

Tumor Necrosis Factor-alpha
Neoplasms
Hypertriglyceridemia
Cachexia
Humoral Hypercalcemia Of Malignancy
Leydig Cell Tumor
Bone and Bones
Organ Culture Techniques
Bone Resorption
Conditioned Culture Medium
Cricetulus
Nude Mice
Radioimmunoassay
Culture Media
Homeostasis
Macrophages
Cytokines
Calcium

Keywords

  • Cachexia
  • Hypercalcemia
  • Leydig cell tumor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Sabatini, M., Yates, A. J., Garrett, I. R., Chavez, J., Dunn, J. F., Bonewald, L., & Mundy, G. R. (1990). Increased production of tumor necrosis factor by normal immune cells in a model of the humoral hypercalcemia of malignancy. Laboratory Investigation, 63(5), 676-682.

Increased production of tumor necrosis factor by normal immune cells in a model of the humoral hypercalcemia of malignancy. / Sabatini, M.; Yates, A. J.; Garrett, I. R.; Chavez, J.; Dunn, J. F.; Bonewald, Lynda; Mundy, G. R.

In: Laboratory Investigation, Vol. 63, No. 5, 1990, p. 676-682.

Research output: Contribution to journalArticle

Sabatini, M, Yates, AJ, Garrett, IR, Chavez, J, Dunn, JF, Bonewald, L & Mundy, GR 1990, 'Increased production of tumor necrosis factor by normal immune cells in a model of the humoral hypercalcemia of malignancy', Laboratory Investigation, vol. 63, no. 5, pp. 676-682.
Sabatini, M. ; Yates, A. J. ; Garrett, I. R. ; Chavez, J. ; Dunn, J. F. ; Bonewald, Lynda ; Mundy, G. R. / Increased production of tumor necrosis factor by normal immune cells in a model of the humoral hypercalcemia of malignancy. In: Laboratory Investigation. 1990 ; Vol. 63, No. 5. pp. 676-682.
@article{d57a55355b8e4ac884e9a5d09b49eb51,
title = "Increased production of tumor necrosis factor by normal immune cells in a model of the humoral hypercalcemia of malignancy",
abstract = "The rat Leydig cell tumor is a well characterized model of the humoral hypercalcemia of malignancy. The studies reported here were provoked by the observation that tumor-bearing rats become extremely cachectic and develop hypertriglyceridemia as they become hypercalcemic. Since the bone resorbing cytokine tumor necrosis factor (TNF)/cachectin is associated with cachexia and hypertriglyceridemia, we examined hypercalcemic tumor-bearing rats for evidence of increased TNF production using a TNF radioimmunoassay. We found that immunoreactive TNF was increased in the plasma of tumor-bearing rats. The increase in plasma TNF was comparable to that previously shown in hypercalcemic nude mice bearing Chinese hamster ovarian cell tumors transfected with the human TNF gene. There was no detectable TNF activity in tumor culture media which suggested that the tumor itself was not the source of excess TNF production. However, we found that tumor cell conditioned media enhanced the production of TNF activity by normal macrophages in vitro, indicating that increased TNF production in vivo may result from a tumor factor(s) which stimulates TNF production by normal immune cells. When TNF was added together with tumor products to organ cultures of fetal rat long bones, osteoclastic bone resorption was potentiated. These data are consistent with the concept that in this model of the humoral hypercalcemia of malignancy, increased TNF production by normal immune cells is increased, has systemic effects as suggested by cachexia and hypertriglyceridemia, and may work in concert with factors produced directly by tumor cells to overwhelm normal calcium homeostasis.",
keywords = "Cachexia, Hypercalcemia, Leydig cell tumor",
author = "M. Sabatini and Yates, {A. J.} and Garrett, {I. R.} and J. Chavez and Dunn, {J. F.} and Lynda Bonewald and Mundy, {G. R.}",
year = "1990",
language = "English (US)",
volume = "63",
pages = "676--682",
journal = "Laboratory Investigation",
issn = "0023-6837",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Increased production of tumor necrosis factor by normal immune cells in a model of the humoral hypercalcemia of malignancy

AU - Sabatini, M.

AU - Yates, A. J.

AU - Garrett, I. R.

AU - Chavez, J.

AU - Dunn, J. F.

AU - Bonewald, Lynda

AU - Mundy, G. R.

PY - 1990

Y1 - 1990

N2 - The rat Leydig cell tumor is a well characterized model of the humoral hypercalcemia of malignancy. The studies reported here were provoked by the observation that tumor-bearing rats become extremely cachectic and develop hypertriglyceridemia as they become hypercalcemic. Since the bone resorbing cytokine tumor necrosis factor (TNF)/cachectin is associated with cachexia and hypertriglyceridemia, we examined hypercalcemic tumor-bearing rats for evidence of increased TNF production using a TNF radioimmunoassay. We found that immunoreactive TNF was increased in the plasma of tumor-bearing rats. The increase in plasma TNF was comparable to that previously shown in hypercalcemic nude mice bearing Chinese hamster ovarian cell tumors transfected with the human TNF gene. There was no detectable TNF activity in tumor culture media which suggested that the tumor itself was not the source of excess TNF production. However, we found that tumor cell conditioned media enhanced the production of TNF activity by normal macrophages in vitro, indicating that increased TNF production in vivo may result from a tumor factor(s) which stimulates TNF production by normal immune cells. When TNF was added together with tumor products to organ cultures of fetal rat long bones, osteoclastic bone resorption was potentiated. These data are consistent with the concept that in this model of the humoral hypercalcemia of malignancy, increased TNF production by normal immune cells is increased, has systemic effects as suggested by cachexia and hypertriglyceridemia, and may work in concert with factors produced directly by tumor cells to overwhelm normal calcium homeostasis.

AB - The rat Leydig cell tumor is a well characterized model of the humoral hypercalcemia of malignancy. The studies reported here were provoked by the observation that tumor-bearing rats become extremely cachectic and develop hypertriglyceridemia as they become hypercalcemic. Since the bone resorbing cytokine tumor necrosis factor (TNF)/cachectin is associated with cachexia and hypertriglyceridemia, we examined hypercalcemic tumor-bearing rats for evidence of increased TNF production using a TNF radioimmunoassay. We found that immunoreactive TNF was increased in the plasma of tumor-bearing rats. The increase in plasma TNF was comparable to that previously shown in hypercalcemic nude mice bearing Chinese hamster ovarian cell tumors transfected with the human TNF gene. There was no detectable TNF activity in tumor culture media which suggested that the tumor itself was not the source of excess TNF production. However, we found that tumor cell conditioned media enhanced the production of TNF activity by normal macrophages in vitro, indicating that increased TNF production in vivo may result from a tumor factor(s) which stimulates TNF production by normal immune cells. When TNF was added together with tumor products to organ cultures of fetal rat long bones, osteoclastic bone resorption was potentiated. These data are consistent with the concept that in this model of the humoral hypercalcemia of malignancy, increased TNF production by normal immune cells is increased, has systemic effects as suggested by cachexia and hypertriglyceridemia, and may work in concert with factors produced directly by tumor cells to overwhelm normal calcium homeostasis.

KW - Cachexia

KW - Hypercalcemia

KW - Leydig cell tumor

UR - http://www.scopus.com/inward/record.url?scp=0025201565&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025201565&partnerID=8YFLogxK

M3 - Article

C2 - 2232714

AN - SCOPUS:0025201565

VL - 63

SP - 676

EP - 682

JO - Laboratory Investigation

JF - Laboratory Investigation

SN - 0023-6837

IS - 5

ER -