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The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics.

Hammond E, Khurana A, Shridhar V, Dredge K - Front Oncol (2014)

Bottom Line: The modification of HSPGs in the tumor microenvironment is known to result not just in structural but also functional consequences, which significantly impact cancer progression.Such observations are consistent with the degradation of normal architecture and basement membranes, which are typically compromised in metastatic disease.Thus, as the influence of the tumor microenvironment in cancer progression becomes more apparent, the focus on targeting enzymes that degrade HSPGs highlights one approach to maintain normal tissue architecture, inhibit tumor progression, and block metastasis.

View Article: PubMed Central - PubMed

Affiliation: Progen Pharmaceuticals Ltd. , Brisbane, QLD , Australia.

ABSTRACT
Heparan sulfate proteoglycans (HSPGs) are an integral and dynamic part of normal tissue architecture at the cell surface and within the extracellular matrix. The modification of HSPGs in the tumor microenvironment is known to result not just in structural but also functional consequences, which significantly impact cancer progression. As substrates for the key enzymes sulfatases and heparanase, the modification of HSPGs is typically characterized by the degradation of heparan sulfate (HS) chains/sulfation patterns via the endo-6-O-sulfatases (Sulf1 and Sulf2) or by heparanase, an endo-glycosidase that cleaves the HS polymers releasing smaller fragments from HSPG complexes. Numerous studies have demonstrated how these enzymes actively influence cancer cell proliferation, signaling, invasion, and metastasis. The activity or expression of these enzymes has been reported to be modified in a variety of cancers. Such observations are consistent with the degradation of normal architecture and basement membranes, which are typically compromised in metastatic disease. Moreover, recent studies elucidating the requirements for these proteins in tumor initiation and progression exemplify their importance in the development and progression of cancer. Thus, as the influence of the tumor microenvironment in cancer progression becomes more apparent, the focus on targeting enzymes that degrade HSPGs highlights one approach to maintain normal tissue architecture, inhibit tumor progression, and block metastasis. This review discusses the role of these enzymes in the context of the tumor microenvironment and their promise as therapeutic targets for the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus

Mechanisms whereby heparanase, Sulf1, and Sulf2 regulate HS function to promote or inhibit tumor growth and spread. (A) HS modification by these three enzymes can have promoting or inhibiting effects on growth factor (GF) signaling. (B) Heparanase, in association with sheddases, can stimulate HSPG shedding, dispersing autocrine to paracrine signaling. (C) Heparanase and Sulf2 can up-regulate HSPG expression to promote GF signaling. And (D) heparanase can induce exosome secretion allowing tumor cell communication with neighboring cells.
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Figure 1: Mechanisms whereby heparanase, Sulf1, and Sulf2 regulate HS function to promote or inhibit tumor growth and spread. (A) HS modification by these three enzymes can have promoting or inhibiting effects on growth factor (GF) signaling. (B) Heparanase, in association with sheddases, can stimulate HSPG shedding, dispersing autocrine to paracrine signaling. (C) Heparanase and Sulf2 can up-regulate HSPG expression to promote GF signaling. And (D) heparanase can induce exosome secretion allowing tumor cell communication with neighboring cells.

Mentions: Heparanase, Sulf1, and Sulf2 have been shown, by virtue of their enzymatic modification of the ECM, to affect the signaling of a number of proteins that are important drivers of tumor growth or progression. In some instances, the signaling function of heparanase may be involved in driving these changes, but it is accepted that heparanase cleavage of HS also plays a significant role in modulating signal transduction. These three enzymes accomplish this modulation in signaling in a number of ways (Figure 1). Firstly, heparanase and Sulf activity modifies the HS component of the ECM, thus altering the interactions between signaling molecules and their receptors. Secondly, heparanase is closely linked to the process of syndecan shedding, particularly syndecan-1, which can be important in changing the focus of a signaling stimulus, for example from autocrine to paracrine. Thirdly, heparanase and Sulf2 regulate expression of HSPG at the cell surface, thus promoting HS-dependant signaling. And fourthly, heparanase is involved in exosome formation by cancer cells, which has recently been shown to promote tumor progression by acting upon both cancerous and stromal cells.


The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics.

Hammond E, Khurana A, Shridhar V, Dredge K - Front Oncol (2014)

Mechanisms whereby heparanase, Sulf1, and Sulf2 regulate HS function to promote or inhibit tumor growth and spread. (A) HS modification by these three enzymes can have promoting or inhibiting effects on growth factor (GF) signaling. (B) Heparanase, in association with sheddases, can stimulate HSPG shedding, dispersing autocrine to paracrine signaling. (C) Heparanase and Sulf2 can up-regulate HSPG expression to promote GF signaling. And (D) heparanase can induce exosome secretion allowing tumor cell communication with neighboring cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109498&req=5

Figure 1: Mechanisms whereby heparanase, Sulf1, and Sulf2 regulate HS function to promote or inhibit tumor growth and spread. (A) HS modification by these three enzymes can have promoting or inhibiting effects on growth factor (GF) signaling. (B) Heparanase, in association with sheddases, can stimulate HSPG shedding, dispersing autocrine to paracrine signaling. (C) Heparanase and Sulf2 can up-regulate HSPG expression to promote GF signaling. And (D) heparanase can induce exosome secretion allowing tumor cell communication with neighboring cells.
Mentions: Heparanase, Sulf1, and Sulf2 have been shown, by virtue of their enzymatic modification of the ECM, to affect the signaling of a number of proteins that are important drivers of tumor growth or progression. In some instances, the signaling function of heparanase may be involved in driving these changes, but it is accepted that heparanase cleavage of HS also plays a significant role in modulating signal transduction. These three enzymes accomplish this modulation in signaling in a number of ways (Figure 1). Firstly, heparanase and Sulf activity modifies the HS component of the ECM, thus altering the interactions between signaling molecules and their receptors. Secondly, heparanase is closely linked to the process of syndecan shedding, particularly syndecan-1, which can be important in changing the focus of a signaling stimulus, for example from autocrine to paracrine. Thirdly, heparanase and Sulf2 regulate expression of HSPG at the cell surface, thus promoting HS-dependant signaling. And fourthly, heparanase is involved in exosome formation by cancer cells, which has recently been shown to promote tumor progression by acting upon both cancerous and stromal cells.

Bottom Line: The modification of HSPGs in the tumor microenvironment is known to result not just in structural but also functional consequences, which significantly impact cancer progression.Such observations are consistent with the degradation of normal architecture and basement membranes, which are typically compromised in metastatic disease.Thus, as the influence of the tumor microenvironment in cancer progression becomes more apparent, the focus on targeting enzymes that degrade HSPGs highlights one approach to maintain normal tissue architecture, inhibit tumor progression, and block metastasis.

View Article: PubMed Central - PubMed

Affiliation: Progen Pharmaceuticals Ltd. , Brisbane, QLD , Australia.

ABSTRACT
Heparan sulfate proteoglycans (HSPGs) are an integral and dynamic part of normal tissue architecture at the cell surface and within the extracellular matrix. The modification of HSPGs in the tumor microenvironment is known to result not just in structural but also functional consequences, which significantly impact cancer progression. As substrates for the key enzymes sulfatases and heparanase, the modification of HSPGs is typically characterized by the degradation of heparan sulfate (HS) chains/sulfation patterns via the endo-6-O-sulfatases (Sulf1 and Sulf2) or by heparanase, an endo-glycosidase that cleaves the HS polymers releasing smaller fragments from HSPG complexes. Numerous studies have demonstrated how these enzymes actively influence cancer cell proliferation, signaling, invasion, and metastasis. The activity or expression of these enzymes has been reported to be modified in a variety of cancers. Such observations are consistent with the degradation of normal architecture and basement membranes, which are typically compromised in metastatic disease. Moreover, recent studies elucidating the requirements for these proteins in tumor initiation and progression exemplify their importance in the development and progression of cancer. Thus, as the influence of the tumor microenvironment in cancer progression becomes more apparent, the focus on targeting enzymes that degrade HSPGs highlights one approach to maintain normal tissue architecture, inhibit tumor progression, and block metastasis. This review discusses the role of these enzymes in the context of the tumor microenvironment and their promise as therapeutic targets for the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus