Autocrine Transforming Growth Factor-beta Growth Pathway in Murine Osteosarcoma Cell Lines Associated with Inability

F Navid1, J J Letterio, C L Yeung

  • 1Pediatric Oncology Branch National Cancer Institute National Institutes of Health Bethesda MD 20892-1928 USA.

Sarcoma
|June 4, 2008
PubMed

Insights

Transforming growth factor-beta (TGF-beta) drives osteosarcoma growth. Blocking TGF-beta reduced tumor cell proliferation, implicating downstream signaling defects in its lack of growth inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Osteosarcoma progression may involve autocrine transforming growth factor-beta (TGF-beta).
  • TGF-beta influences angiogenesis, immune suppression, and tumor cell growth.

Purpose of the Study:

  • To investigate the TGF-beta pathway in murine osteosarcoma cell lines (K7 and K12).
  • To understand events regulating cell proliferation in response to TGF-beta.

Main Methods:

  • Northern and immunohistochemical analyses for TGF-beta1 and TGF-beta3 expression.
  • Affinity labeling to detect TGF-beta receptors (TbetaRI, TbetaRII, TbetaRIII).
  • Analysis of Smad intermediates (2, 3, 4) and pRb phosphorylation.

Main Results:

  • Both cell lines expressed TGF-beta1 and TGF-beta3 mRNA and protein.
  • Active TGF-beta1 secretion and a 30-50% growth reduction with TGF-beta blocking antibody were observed.
  • Smads 2 and 3 were phosphorylated, but pRb phosphorylation was unaffected by TGF-beta or antibody.

Conclusions:

  • Impaired regulation of pRb downstream of Smad activation contributes to the lack of TGF-beta growth inhibition.
  • This murine osteosarcoma model is suitable for studying autocrine TGF-beta roles in vivo.

Related Concept Videos

TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...