Hyaluronan Mediated Signalling Mechanisms in Cancer

The mechanisms whereby HA receptor mediated effects are translated into cellular signals which coordinate cell communication, movement, growth, survival and transformation are being studied intensely by many research groups. Sohara et al. (93) previously reported that the enhancement of HA-dependent cell movement was affected by the actions of the pan PI3-kinase inhibitor LY294002 or wortmannin suggesting that activation of PI3-kinase by the HA-CD44 interaction was required for cell motility. This observation was tested further to evaluate the effect of PI3-kinase inhibitors on cellular transformation by HAS2 transfectants (32). The inhibition of the PI3-kinase pathway by LY294002 or wortmannin resulted in the HAS2 transfectants reverting from fibroblast shaped cells, which formed overlapping cell layers, to a normal control phenotype. These data highlighted the role of PI3-kinase in the regulation of diminishing contact inhibition induced by formation of increased HA matrix. It will be important to confirm these observations with selective PI3-kinase inhibitors (94).

Other signalling pathways have also been implicated in the HA-CD44 dependent interaction. Cellular transformation by Rous sarcoma virus is mediated via the V-src gene product (95). One of the cellular changes caused by V-src noted many years ago was an accumulation of HA (96) although its role was not clear. Sohara et al. (93) investigated the production of HA on cell motility in cell lines expressing the V-src mutants. The initial observation was that transformation of 3Y1 fibroblast cells by V-src alone activated HA secretion. Additionally, HA treatment caused significant increase in motility of V-src transformed 3Y1 fibroblast cells, which interestingly was inhibited by expression of a dominant negative Ras or treatment with a Ras farnesyltransferase inhibitor. Similarly, a neutralising anti-CD44 antibody also blocked the activation of cell motility and HA-dependent phosphorylation of mitogen activated protein kinase (MAPK) and Akt. This study implicated the simultaneous activation of the Ras-MAPK pathway and the PI3-kinase pathway in HA-CD44 dependent cellular migration.

Increasingly a number of guanine exchange factors (GEFs) have been identified (97) as downstream components of HA-mediated signalling. Evidence of Rac-1 signalling upon binding of HA with CD44 and its effect on tumour cell activation have been described above. Additionally Tiam 1, which is another GEF, was reported to interact with CD44v3 and to up-regulate Rac-1 signalling and cytoskeletal-mediated metastatic breast cancer progression (98). In a continued search for other CD44 isoform-linked GEFs, which correlated with tumour metastasis, Vav2 was identified (99). This group carefully dissected the interaction of CD44v3 and Vav2 and proposed that CD44v3-Vav2 interacts with Grb2-p185HER2 to form a signalling complex that had a pivotal role in promoting cross-talk between RAC1 and Ras signalling pathways, ultimately causing the migration and growth of ovarian cancer.

With the elucidation of CD44 isoforms, and the identification of an increasing number of GEFs, it is apparent that specific CD44 isoforms mediate different functions, including malignant transformation (e.g., CD44v) in different cancers by interactions with specific GEFs. A unique mechanism involving CD44-HA interaction with RhoGEF and Rho kinase was described by Bourguignon et al. (100), which showed that this complex stimulated Gab-1 phosphorylation and membrane localisation. This in turn caused PI3-kinase and Akt activation, and ultimately macrophage colony stimulating factor production in breast cancer cells.

The importance of CD44-HA interaction and signalling in tumorigenesis is clearly an emerging and important area of research and has primarily been studied in the context of cellular growth and motility. However, the impact of CD44-HA interaction on the destruction of the cellular matrix is also being realised. Matrix degrading enzymes such as the family of matrix metallopro-teases have a critical role in invasion and metastasis and matrix components such as fibronectin are known to activate matrix metalloprotease-9 (MMP-9) secretion via MEK1-MAPK and the PI3-kinase/Akt signalling pathways (101). Similarly, HA as a major component of the ECM was shown to activate MMP-2 secretion in a focal adhesion kinase (FAK)-MAPK dependent manner in the QG90 lung carcinoma cell line (102). This lung carcinoma is known to express large amounts of CD44s and interestingly, HA-dependent MMP-2 secretion and subsequent cell invasion were inhibited by several methods including anti-CD44 antibody treatment, expression of antisense CD44 or by the pan PI3-kinase inhibitor, wortmannin (103). It appears from these studies that HA-dependent invasion and MMP-2 secretion requires dual signalling pathways, MEK1-MAPK and PI3-kinase. The regulation of HA induced MMP activity is poorly understood but recently it was proposed that the tumour suppressor gene, PTEN may have a role in reducing HA induced MMP-9 secretion in glioblastoma cells by dephos-phorylation of FAK in U87MG glioblastoma cells (104). PTEN is a lipid phosphatase that degrades phosphoinositide 3,4,5-triphosphate, a signalling product of the action of PI3-kinase. There is some debate, however, on the importance of the lipid phosphatase activity of PTEN in the regulation of MMP secretion and potential invasion of glioma cells. Studies have shown that this activity is essential (105); conversely other studies have shown that PTEN lipid phosphatase is not required for invasion of glioma cells (106). An overview of some of the HA-mediated signalling pathways involved in cancer are shown in Fig. 1. Clearly major advances in the understanding of HA-mediated signalling events and tumour cell progression have been made; however, further identification of the downstream signalling molecules, their context in pathways and the extent of cross talk of signals that are involved in HA-mediated tumour invasion have yet to be determined.

This chapter has focused primarily on reports using native HA. It is, however, known that fragmented HA also has specific effects on tumour cells. The association of low MW HA on tumour cell proliferation, migration, and angiogenesis was presented above. Additionally it has been shown that fragmented HA also has effects on signalling pathways. CD44 stimulated by fragmented HA induced up-regulation of tyrosine phosphorylation of the c-Met

Cytoskeletal effects, Motility migration Tumour Cell growth

Figure 1 Overview of hyaluronan-mediated signalling mechanisms in cancer. Hyaluronan has been shown to have many effects on signalling cascades. Both native and low MW hyaluronan have been shown to elicit signalling events via hyaluronan receptors such as CD44 or RHAMM or by undefined mechanisms which ultimately affect tumour cell growth, migration, or angiogenesis. HA: hyaluronan; TGFb transforming growth factor beta; ERM: ezrin, radixin, moesin family of proteins; PKs: protein kinases, e.g., PI3-kinase pathway; FAK-MAP: kinase pathway; GEFs: guanine exchange factors, e.g., Tiam 1, Vav2; MMP: matrix metalloprotease; PLCg: phospholipase C gamma; PDGF: platelet-derived growth factor receptor.

Cytoskeletal effects, Motility migration Tumour Cell growth

Figure 1 Overview of hyaluronan-mediated signalling mechanisms in cancer. Hyaluronan has been shown to have many effects on signalling cascades. Both native and low MW hyaluronan have been shown to elicit signalling events via hyaluronan receptors such as CD44 or RHAMM or by undefined mechanisms which ultimately affect tumour cell growth, migration, or angiogenesis. HA: hyaluronan; TGFb transforming growth factor beta; ERM: ezrin, radixin, moesin family of proteins; PKs: protein kinases, e.g., PI3-kinase pathway; FAK-MAP: kinase pathway; GEFs: guanine exchange factors, e.g., Tiam 1, Vav2; MMP: matrix metalloprotease; PLCg: phospholipase C gamma; PDGF: platelet-derived growth factor receptor.

receptor (107), activation of MAPK with subsequent enhancement of urokinase-type 1 plasminogen activator and its receptor which ultimately facilitated invasion of human chondrosarcoma cells (108). Clearly fragmented HA, similar to native HA, is also able to initiate signal transduction cascades or promote cross talk originating from CD44-HA interactions.

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