Posted by: Dan | May 6, 2006

Recent paper on PDGF in TGFbeta-mediated EMT in hepatocytes

In an advanced online publication in Oncogene in April, the group that wrote a nice review of the epithelial to mesenchymal transition in 2004 came out with a paper on A crucial function of PDGF in TGFbeta-mediated cancer progression of hepatocytes.

As described recently in both hepatocytes (specialized liver cells) and breast epithelial cells, hyperactive Ras and transforming growth factor (TGF)beta synergistically promote cancer progression through acquisition of a metastatic growth behavior, functional de-differentiation, resistance to apoptosis, and modulations of transcription factors involved in the expression of junctional proteins. Gotzmann et al., working with Wolfgang Mikulits at the University of Vienna, have developed a cellular EMT model unique to hepatocytes that is driven by this collaboration of Ras and TGFbeta, which they then used to monitor global expression patterns employing oligo-microarray analysis. Their findings included elevated levels of platelet-derived growth factor (PDGF)-A and PDGF Receptor upon EMT, along with a TGFbeta-induced secretion of PDGF-A.

Basically, that’s it – for those laypersons out there, primary research articles are generally just that: frequently they make a brief case, with a few complementary pieces of evidence, for one or two new findings. Kind of like a building a house out of bricks, where each paper is a single (or maybe two) bricks. As you can imagine, it takes a while.

But on to the paper: Gotzmann et al. started with the finding that the three isoforms of TGFbeta equally induced EMT, whereas other members of the TGFbeta superfamily did not, in hepatocytes, as well as mammary and lung epithelial cell lines, but not keratinocytes (oversimplifyingly, keratinocytes are other epithelial cell types). Examining of the sequence of known molecular events associated with TGFbeta-induction of EMT, suggested that a “complex interplay of transcription factors and associated molecules is instrumental in regulating most cell adhesion properties in the transition from an EMT phenotype in hepatocytes,” and that these transcriptional activities occurred within 24h of this TGFbeta-induction, whereas the transition reached a maintenance phase by 72h, and was complete by 120h.

From this information, Gotzmann et al. tried expression profiling, screening the ‘active’ transcriptome by hybridization of polysome-bound mRNA populations, comparing expression of an array of proteins at 24h, 72h, and 120h. This procedure showed, among other things, that the PDGF-A ligand and both receptor subunits were expressed at highly elevated levels upon TGFbeta-induction of EMT in their hepatocellular EMT model, agreeing with previous reports, and similar upregulation of the entire PDGF signaling pathway by expression profiling of Ras/TGFbeta-induced EMT in a mammary epithelial cell model. PDGF signaling stimulates various signaling pathways including Ras-MAP kinase, the PI3 kinase, the phospholipase Cgamma, the cytoplasmic tyrosine kinase c-Src and different Stats. Combined with the dual role of the Ras-MAPK pathway in both proliferation and metastasis, and PDGF-derived PI3K upregulation in blocking apoptosis, this makes PDGF-activation an attractive mechanistic explanation for how the TGFbeta-induction might be furthering cancer progression in ways other than just disrupting cell-cell contacts.

Significance

While the correlation of upregulated receptor tyrosine kinases (RTKs) like PDGF with a wide variety of cancers is well documented, the linkage of PDGF with Ras/TGFbeta-induced EMT is a novel finding, representing another link in the complex biochemistry existing in mammalian cells and a specific event in the progression of hepatocellular carcinoma (HCC). Understanding how this vast array of protein interactions is interrelated, and perturbed on a cellular scale by one or two small pathological mutations, aids oncologists and drug designers with the knowledge to devise an effective therapeutic rationale, afterall.

My Interpretation

Gotzmann et al. describe a screen for yet another protein interaction with potential significance for cancer therapeutics. The literature is abound with such studies, and all of them are important. But the reality is that signal transduction doesn’t occur in straightforward pathways – from a biochemical standpoint, the cell is a heterogeneous soup, with multiple critical regulators and effectors for each protein of importance – the cell’s proteome is a vast network of interactions, and this is of course where bioinformatics comes in. Indeed, some of the studies that most impress me are mathematical and computer modeling of these networks, and important “nodal points,” or key proteins, and the potential ways in which cellular microenvironments pull the strings on this network.

But don’t forget, discovery of novel interactions and transcription events are what makes this bioinformatics run – making Gotzmann et al. an important contribution.

Confused yet? Me too! (just hopefully less so than most people)

References

  • A crucial function of PDGF in TGF-beta-mediated cancer progression of hepatocytes. Gotzmann J, Fischer AN, Zojer M, Mikula M, Proell V, Huber H, Jechlinger M, Waerner T, Weith A, Beug H, Mikulits W. Oncogene. 2006 Apr 10; [Epub ahead of print]. Pubmed

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