Role of Versican, Hyaluronan and CD44 in Ovarian Cancer Metastasis

Ween, Miranda P.; Oehler, Martin K.; Ricciardelli, Carmela

doi:10.3390/ijms12021009

Cited by 113 publications

(94 citation statements)

References 118 publications

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“…The majority of HA is localized in tumor ECM, where it binds with multiple hyaladherins or hyalectans (5,6,37,38). Versican is predominantly expressed in HA high tumors (5,37,38) and has limited commercial availability.…”

Section: Discussionmentioning

confidence: 99%

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Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Singha

Nekoroski

Zhao

et al. 2015

Molecular Cancer Therapeutics

116

101

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Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HA high ) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to mAb therapy. We determined that approximately 60% of HER2 3þ primary breast tumors and approximately 40% of EGFR þ head and neck squamous cell carcinomas are HA high , and hypothesized that HA high tumors may be refractory to mAb therapy. We found that the pericellular matrix produced by HA high tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HA high tumor cells, and greatly enhanced trastuzumab-or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HA high tumors, resulting in enhanced trastuzumab-and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HA high matrix in vivo may form a barrier inhibiting access of both mAb and NK cells, and that PEGPH20 treatment in combination with anticancer mAbs may be an effective adjunctive therapy for HA high tumors.

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Section: Discussionmentioning

confidence: 99%

“…Versican is predominantly expressed in HA high tumors (5,37,38) and has limited commercial availability. Aggrecan is a proteoglycan with structure composition similar to versican and binds to HA efficiently and was used in the in vitro studies reported here.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Singha

Nekoroski

Zhao

et al. 2015

Molecular Cancer Therapeutics

116

101

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“…On the other hand, versican expression correlates with a poor prognosis in many cancer types (301,325). This proteoglycan interacts with multiple ECM and cell surface components, promoting cell proliferation, cell motility, and metastasis (301,310,382). Intriguingly, in breast cancer, versican has been associated with chemotherapy resistance related to EGFR hypersignaling and enhanced cancer cell self-renewal (78,79).…”

Section: Proteoglycansmentioning

confidence: 99%

“…In general, accumulation of HA in tissues where it is normally absent facilitates tumor growth (i.e., gastric cancers), while reduced HA is associated with cancer in normally HArich stratified epithelia containing tissues such as skin, mouth, and larynx (355). Interestingly, epithelial HA accumulation in colon cancer constitutes a bad prognostic occurrence (304), while stromal HA buildups have been associated with an unfavorable prognosis in ovarian, prostate, breast, and nonsmall cell lung cancers (11,217,289,382). In the case of liver, the main organ in charge of processing HA (98), a large synthesis of the glycosaminoglycan and increasing circulating levels of HA have been found to correlate with liver fibrosis (cirrhosis) (280).…”

Section: Hyaluronanmentioning

confidence: 99%

The wound healing, chronic fibrosis, and cancer progression triad

Rybinski

Franco‐Barraza

Cukierman

2014

Physiological Genomics

215

175

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For decades tumors have been recognized as “wounds that do not heal.” Besides the commonalities that tumors and wounded tissues share, the process of wound healing also portrays similar characteristics with chronic fibrosis. In this review, we suggest a tight interrelationship, which is governed as a concurrence of cellular and microenvironmental reactivity among wound healing, chronic fibrosis, and cancer development/progression (i.e., the WHFC triad). It is clear that the same cell types, as well as soluble and matrix elements that drive wound healing (including regeneration) via distinct signaling pathways, also fuel chronic fibrosis and tumor progression. Hence, here we review the relationship between fibrosis and cancer through the lens of wound healing.

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“…However, an emerging theme is that many such structural proteoglycans have, in addition, signaling roles, particularly with respect to the immune system. Versican has been identified as upregulated in many tumors, including, lung, gastric, ovarian, breast, and melanoma (Kim S et al 2009;Ricciardelli et al 2009;Du et al 2010;Ween et al 2011, Hernández et al 2011. In 2009, it was identified as a macrophage activator, through cell surface TLR2:TLR6 complexes that in turn induced TNF-α secretion by myeloid cells, with downstream promotion of lung cancer metastasis (Kim S et al 2009).…”

Section: Proteoglycans and Acquired Diseasesmentioning

confidence: 99%

An Introduction to Proteoglycans and Their Localization

Couchman

Pataki

2012

J Histochem Cytochem.

171

155

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SummaryProteoglycans comprise a core protein to which one or more glycosaminoglycan chains are covalently attached. Although a small number of proteins have the capacity to be glycanated and become proteoglycans, it is now realized that these macromolecules have a range of functions, dependent on type and in vivo location, and have important roles in invertebrate and vertebrate development, maintenance, and tissue repair. Many biologically potent small proteins can bind glycosaminoglycan chains as a key part of their function in the extracellular matrix, at the cell surface, and also in some intracellular locations. Therefore, the participation of proteoglycans in disease is receiving increased attention. In this short review, proteoglycan structure, function, and localizations are summarized, with reference to accompanying reviews in this issue as well as other recent literature. Included are some remarks on proteoglycan and glycosaminoglycan localization techniques, with reference to the special physicochemical properties of these complex molecules. (J Histochem Cytochem 60:885-897, 2012)

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Role of Versican, Hyaluronan and CD44 in Ovarian Cancer Metastasis

Cited by 113 publications

References 118 publications

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

The wound healing, chronic fibrosis, and cancer progression triad

An Introduction to Proteoglycans and Their Localization

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