Biomedical Engineering Reference
In-Depth Information
Chapter 2
2.1 Biological Introduction
Hepatocyte growth factor (HGF), originally identified as a mitogen for hep-
atocytes [271, 288], was subsequently shown to be identical to scatter factor
(SF) [45, 92, 97], a ligand able to induce epithelial cell dissociation [91]. HGF,
produced primarily by mesenchymal cells, is therefore a unique growth fac-
tor that elicits multiple cellular responses via its receptor, a tyrosine kinase
encoded by the proto-oncogene Met [257, 288]. The main biological processes
regulated by HGF are mitogenesis, motility and morphogenesis [389, 394], cell
dissociation, migration through the extracellular matrix, acquisition of polar-
ity, and tubule formation [338, 380]. This combination of events, also known
as invasive growth, is fundamental during the embryonic development of most
epithelial tissues. When inappropriately activated, this genetic program con-
fers invasive ability to normal and neoplastic epithelial cells [271, 407].
Overexpressions of the HGF receptor Met have been observed in primary
thyroid cells [223, 261], suggesting that Met may mediate some of the pheno-
typic alterations observed in these cells: these data allow one to precisely define
the role of the HGF and its receptor in the evolution of thyroid tumors, finding
which of the many cellular events known to follow Met activation effectively
take place in thyroid cancer cells. Indeed, an experimental model of a poorly
differentiated thyroid carcinoma-derived cell line, ARO, provides evidence
that HGF stimulation does not increase the growth rate, probably due to the
high basal level of proliferation, but it increases motility [101, 104]. In partic-
ular, HGF induces a mesenchymal transition with a dramatic change from a
virtually nonmotile phenotype to a phenotype with high short-range motility:
cells loosen contacts, dissociate, move from their original site and start wander-
ing in close proximity, displaying an evident ability to invade the open spaces
and modifying the interaction with the extracellular matrix; see Figure 2.1 (the
full time-lapse movie is available at calvino.polito.it/preziosi/AROex.avi). It
is noteworthy that in response to HGF, ARO cells do not show a dramatic cy-
toskeletal reorganization or polarization but lose their tendency to maximize
the contact area with the surrounding cells and the physiological regulation of
contact inhibition mechanism. The change in the above-mentioned adhesive
properties is a consequence of the change in the transmission of a number
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