Tumor-Derived Growth Factor Increases Bone Resorption in a Tumor Associated with Humoral Hypercalcemia of Malignancy

Ibbotson, K J; D'Souza, S M; Ng, KW; Ck, Osborne; Niall, M; Martin, T. J.; Gr, Mundy

doi:10.1126/science.6577602

Cited by 119 publications

(37 citation statements)

References 12 publications

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“…This is approximately the time when in rat gestation the levels of TGFa mRNA have declined. An alternate explanation is suggested by studies which implicate the action of TGFa in the process of bone resorption (7,8). Consistent with this model, the expression of TGFa in embryos may be instrumental in the embryonic remodeling which occurs during development.…”

mentioning

confidence: 68%

Developmental expression of rat transforming growth factor-alpha mRNA.

Lee¹,

Rochford²,

Todaro³

et al. 1985

Mol. Cell. Biol.

150

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Expression of the gene encoding transforming growth factor-a (TGFa) was examined in developing rat embryos by using a cloned TGFo cDNA as a hybridization probe. Northern blot analysis of RNA isolated from whole fetuses revealed that TGFaL mRNA was present at relatively high levels in 8-through 10-day-old embryos and then declined to the low or undetectable level, which is characteristic of adult tissues before birth. The level of TGFcc mRNA present during early gestation was similar to that present in retrovirus-transformed cells in culture, suggesting that TGFa expression is not highly localized in the embryo. These observations are consistent with the hypothesis that TGFat plays a role in development, possibly as a fetal growth factor.Transforming growth factors (TGFs) are potent mitogenic polypeptides produced by a variety of retrovirustransformed cells and certain tumors (17). In addition, TGFs confer on normal cells in culture some of the phenotypic properties associated with transformation, including loss of contact inhibition and growth in soft agar (3). Two distinct types of TGFs have been identified. TGFa is structurally related to epidermal growth factor (EGF) (6,11,12,15) and competes for binding to the EGF receptor (13). TGF,B, on the other hand, potentiates the growth-stimulating activity of TGFa and demonstrates no affinity for the EGF receptor (1).Recently, cDNA clones encoding human (4) and rat (9) TGFs's have been isolated; the nucleotide sequence of these cDNAs suggests that human and rat TGFs's are initially synthesized as polypeptides of 160 and 159 amino acids, respectively, and that these larger forms exist as transmembrane proteins. Release of the smaller TGFa from the larger form apparently does not occur through the action of a serine-like protease but, rather, through an unusual proteolytic cleavage between alanine and valine residues at both the amino and carboxy termini of the rat and human molecules.Using the cloned rat TGFa cDNA as a hybridization probe, we have previously shown that retrovirustransformed cells express a 4.5-kilobase TGFa mRNA (9). A similar-sized transcript is also detected at considerably lower levels in some adult rat tissues but not in the corresponding untransformed cell line. Here we report that Northern analysis of developing rat embryos indicates that TGFa transcripts are expressed at relatively high levels during early embryogenesis but then decline to low levels before birth. These results are consistent with the hypothesis that TGFa functions as a developmental growth factor.Pools of rat embryos were collected at various time points from time-mated Sprague-Dawley rats. RNA was isolated by homogenization of embryos or cells in 4 M guanidine * Corresponding author. Medicine, Chapel Hill, NC 27514. thiocyanate and sedimentation through 5.7 M CsCl (2, 5).Poly(A)' RNA was selected by chromatography on oligo(dT)-cellulose, and samples (5 ,ug) were electrophoresed through 1% agarose gels containing formaldehyde (10). RNA was transferred to nitrocellulose and...

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mentioning

confidence: 68%

Developmental expression of rat transforming growth factor-alpha mRNA.

Lee¹,

Rochford²,

Todaro³

et al. 1985

Mol. Cell. Biol.

150

View full text Add to dashboard Cite

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“…Attention, therefore, has been focused on TGF-a as a possible mediator of increased bone resorption in the humoral hypercalcemia of malignancy (12)(13)(14)(15). However, the underlying mechanism responsible for TGF-a-induced osteoclastic bone resorption is unknown.…”

Section: Introductionmentioning

confidence: 99%

Recombinant human transforming growth factor-alpha stimulates the formation of osteoclast-like cells in long-term human marrow cultures.

Takahashi¹,

MacDonald²,

Hon³

et al. 1986

J. Clin. Invest.

112

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Transforming growth factor-alpha (TGF-a) is synthesized by a variety of tumor cell lines and stimulates osteoclastic bone resorption in vitro. The mechanism by which TGF-a increases osteoclast activity is unknown. We used a human marrow culture system that forms osteoclast-like multinucleated cells (MNCs) to determine the effects of recombinant human TGF-a on MNC formation. Addition of 0.01 ng/ml TGF-a for the 1st week followed by 1,25-dihydroxyvitamin D3 I1,25(0H)2D31 for the subsequent 2 wk significantly increased MNCs. Treatment of these cultures with TGF-a without later addition of 1,25(0H)2D3 did not increase MNC formation. Autoradiographic studies revealed that TGF-a stimulated proliferation of precursors for MNCs, and 1,25(OH)2D3 increased their rate of fusion into MNCs. Addition of murine epidermal growth factor (EGF) (0.1 ng/ml) followed by 1,25(OH)2D3 also significantly stimulated MNC formation. These data suggest that TGF-a and EGF may stimulate bone resorption by increasing the proliferation of osteoclast precursors, which leads to increased numbers of osteoclasts.

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“…As with EGF, TGF-alpha-mediated resorption is dependent on prostaglandin synthesis in newborn mouse calvaria cultures and independent of prostaglandin synthesis in fetal rat long-bone cultures. TGF-alpha is synthesized and released from a number of neoplasms including the Rice Leydig Cell Tumor, a malignancy which produces humorally mediated hypercalcemia in rats (31). Antibodies to the EGF receptor block the in vitro bone resorbing activity of supernatants derived from cultured Rice Leydig cells (32).…”

Section: Discussionmentioning

confidence: 99%

Effects of DNA and prostaglandin synthesis inhibitors on the stimulation of bone resorption by epidermal growth factor in fetal rat long-bone cultures.

Lorenzo¹,

Quinton²,

Sousa³

et al. 1986

J. Clin. Invest.

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We examined two inhibitors of DNA synthesis, hydroxyurea (HU) and aphidicholin (APC), and two inhibitors of prostaglandin cyclooxygenase, indomethacin and flufenamic acid, for their effects on the resorptive responses of fetal rat long-bone cultures to epidermal growth factor (EGF) and parathyroid hormone (PTH).As These results demonstrate that the mechanisms regulating PTH-and EGF-mediated resorption in fetal rat long-bone cultures differ, and imply that a component of EGF-mediated resorption in these cultures is dependent on sustained DNA synthesis.

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Tumor-Derived Growth Factor Increases Bone Resorption in a Tumor Associated with Humoral Hypercalcemia of Malignancy

Cited by 119 publications

References 12 publications

Developmental expression of rat transforming growth factor-alpha mRNA.

Developmental expression of rat transforming growth factor-alpha mRNA.

Recombinant human transforming growth factor-alpha stimulates the formation of osteoclast-like cells in long-term human marrow cultures.

Effects of DNA and prostaglandin synthesis inhibitors on the stimulation of bone resorption by epidermal growth factor in fetal rat long-bone cultures.

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