Elsevier

Matrix Biology

Volume 24, Issue 6, September 2005, Pages 400-417
Matrix Biology

Mini review
Proteoglycan control of cell movement during wound healing and cancer spreading

https://doi.org/10.1016/j.matbio.2005.06.005Get rights and content

Abstract

By virtue of their multifunctional nature, proteoglycans (PGs) are thought to govern the process of cell movement in numerous physiological and pathological contexts, spanning from early embryonic development to tumour invasion and metastasis. The precise mode by which they influence this process is still fragmentary, but evidence is accruing that they may affect it in a multifaceted manner. PGs bound to the plasma membrane mediate the polyvalent interaction of the cell with matrix constituents and with molecules of the neighbouring cells' surfaces; they modulate the activity of receptors implicated in the recognition of these components; and they participate in the perception and convergence of growth- and motility-promoting cues contributed by soluble factors. Through some of these interactions several PGs transduce to pro-motile cells crucial intracellular signals that are likely to be essential for their mobility. A regulated shedding of certain membrane-intercalated PGs seems to provide an additional level of control of cell movement. Coincidentally, matrix-associated PGs may govern cell migration by structuring permissive and non-permissive migratory paths and, when directly secreted by the moving cells, may alternatively create favourable or hostile microenvironments. To exert this latter, indirect effect on cell movement, matrix PGs strongly rely upon their primary molecular partners, such as hyaluronan, link proteins, tenascins, collagens and low-affinity cell surface receptors, whereas a further finer control is provided by a highly regulated proteolytic processing of the PGs accounted by both the migrating cells themselves and cells of their surrounding tissues. Overall, PGs seem to play an important role in determining the migratory phenotype of a cell by initiating, directing and terminating cell movement in a spatio-temporally controlled fashion. This implies that the “anti-adhesive and/or “anti-migratory” properties that have previously been assigned to certain PGs may be re-interpreted as being a means by which these macromolecules elaborate haptotaxis-like mechanisms imposing directionality upon the moving cells. Since these conditions would allow cells to be led to given tissue locations and become immobilized at these sites, a primary function may be ascribed to PGs in the dictation of a “stop or go” choice of the migrating cells.

Section snippets

Alternative interpretations of the role of PGs in CNS repair

Spinal cord and brain lesion models are currently employed to understand the cellular and molecular mechanisms involved in the potential regeneration of the central nervous system. In experimentally induced tissue damages, axon regeneration appears to be strongly impeded by scarring at the site of injury, which is well documented to imply increased deposition of PGs carrying both CS and KS chains (reviewed by Silver and Miller, 2004). A plethora of studies have now clarified that up-regulation

Are PGs essential for the cell rearrangement occurring during wound healing?

Normal wound healing and tissue repair after acute damage are known to involve the formation of a granulation tissue and the elaboration of a provisional matrix highly enriched in PGs. Subsequent scarring at the site of injury, which is accompanied by different levels of fibrosis, also implies deposition of a PG-containing matrix provided by invading (myo)fibroblasts. Conversely, milder tissue damage, or chronic tissue degeneration, involves remodelling of the existing matrix and an augmented

Dual role of PG-M/versicans in wound healing phenomena

Together with tenascins, hyaluronan and interstitial collagens, PG-M/versicans are the primary matrix molecules to be up-regulated at sites of acute tissue damage and/or chronic tissue degeneration. Their involvement in tissue repair phenomena may entail a higher level of complexity since, in addition to the intricate metalloproteinase- and ADAMTS-dependent cleavage pattern of these PGs following injury (Somerville et al., 2003), there is a diverse regulation of the expression pattern of the

Surface bound and shedded PGs may influence tissue reconstitution by different mechanisms

In the best-studied wound-healing model, i.e. the skin, CD44 is known to play a major role in the fibroblast invasion of the damaged region (Henke et al., 1996). Accordingly, CD44 null mice exhibit partially perturbed wound-healing capacities, which may be reinforced by an abnormal recruitment of anti-inflammatory cells (Schmits et al., 1997). However, in contrast to what could be predicted, it is unlikely that the interaction of the CD44 with hyaluronan may be responsible for apparent

“PG size” makes the difference in the control of tumour invasion and metastatic spread

A characteristic trait of invasive solid tumours is the increased, or de novo induced, expression of several PGs. The majority of these macromolecules derive from a corresponding enhanced transcription in the neoplastic cells themselves, but a substantial contribution to the overall amount of PGs contained within a solid tumour lesion is also frequently afforded by its stromal component. Several investigations have documented that PG-M/versicans are primary constituents of this compartment of

PG-ligand regulatory loops and polarized PG surface distribution are critical for tumour cell motility and invasion

Over expression of CD44, and in particular the CD44v6 alternatively spliced variant, is conventionally believed to be detrimental for cancer patients because it may reflect the presence of more malignant metastatic tumours. Original studies indirectly suggested that CD44 could be implicated in melanoma cell motility and invasion in response to collagen type I substrates and following TGFβ stimulation of the cells (Faassen et al., 1993), and a similar suggestion was made with regard to glioma

Dual function of cell surface PGs in the conversion of transformed cells into motile phenotypes

One of the most classical experiments demonstrating the importance of cell surface PGs in tumour progression, and in particular the role of HS-carrying PGs, was originally performed by Jeffrey Esko and collaborators (Esko et al., 1988). This study highlighted that cells genetically engineered to be defective in the HS biosynthesis, and thereby harbouring a compositional deficit of their surface HSPGs, failed to form tumours both in vitro and in vivo. These findings were strongly corroborated by

Acknowledgments

Unpublished work of the authors' was supported by a number of national and international institutions. Primary financial contributions are currently provided by grants from the Italian Ministry of Health, the Italian Ministry of Education, University and Scientific Research (MIUR, projects FIRB 2001 and PRIN 2004), Associazione Italiana per la Ricerca sul Cancro (AIRC), and intramural research funds from the University of Parma. We are thankful to our numerous collaborators around the world for

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