A STO SE TICE TIH DRUGIH INEKCIJA, HIJALURONA, I OVO TREBA ZNATI
Role in cancer metastasis[edit]
Figure 1. The process of cancer metastasis in which HA-associated molecules play a role in the steps. Abbreviations: hyaluronic acid (HA), hyaluronic acid synthase (HAS), hyaluronic acid receptor (HAR), hyaluronidase (HAase/HYAL)[citation needed] As shown in Figure 1, the various types of molecules that interact with hyaluronan can contribute to many of the stages of cancer metastasis, i.e. further the spread of cancer.[citation needed]
Hyaluronan synthases (HAS) play roles in all of the stages of cancer metastasis. By producing anti-adhesive HA, HAS can allow tumor cells to release from the primary tumor mass, and if HA associates with receptors such as CD44, the activation of Rho GTPases can promote epithelial-mesenchymal transition (EMT) of the cancer cells. During the processes of intravasation or extravasation, the interaction of HAS produced HA with receptors such as CD44 or RHAMM promote the cell changes that allow for the cancer cells to infiltrate the vascular or lymphatic systems. While traveling in these systems, HA produced by HAS protects the cancer cell from physical damage. Finally, in the formation of a metastatic lesion, HAS produces HA to allow the cancer cell to interact with native cells at the secondary site and to produce a tumor for itself.[51]
Hyaluronidases (HAase or HYAL) also play many roles in cancer metastasis. By helping to degrade the extracellular matrix surrounding the tumor, hyaluronidases help the cancer cell escape from the primary tumor mass and play a major role in intravasation by allowing degradation of the basement membrane of the lymph or blood vessel. Hyaluronidases again play these roles in establishment of a metastatic lesion by helping with extravasation and clearing the ECM of the secondary site.[52] Finally, hyaluronidases play a key role in the process of angiogenesis. HA fragments promote angiogenesis and hyaluronidases produce these fragments.[53] Interestingly, hypoxia also increases production of HA and activity of hyaluronidases.[54]
The hyaluronan receptors, CD44 and RHAMM, are most thoroughly studied in terms of their roles in cancer metastasis. Increased clinical CD44 expression has been positively correlated to metastasis in a number of tumor types.[55] In terms of mechanics, CD44 affects adhesion of cancer cells to each other and to endothelial cells, rearranges the cytoskeleton through the Rho GTPases, and increases the activity of ECM degrading enzymes.[56] Increased RHAMM expression has also been clinically correlated with cancer metastasis. In terms of mechanics, RHAMM promotes cancer cell motility through a number of pathways including focal adhesion kinase (FAK), Map kinase (MAPK), pp60(c-src), and the downstream targets of Rho kinase (ROK).[57] RHAMM can also cooperate with CD44 to promote angiogenesis toward the metastatic lesion.[58]
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