4-Methylumbelliferone Abstracts 2


Hyaluronan as an immune regulator in human diseases.
            (Jiang et al., 2011) Download
Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.

The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma.
            (Kudo et al., 2017) Download
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases to affect humans, regardless of whether patients receive multimodal therapy (including surgery, radiotherapy, and chemotherapy). This resistance to intervention is currently considered to be caused by the desmoplastic change of the extracellular matrix (ECM) in PDAC tissues, which is characterized by the accumulation of cancer-associated fibroblasts, collagen, proteoglycan, and hyaluronan. Among these ECM components, hyaluronan has attracted interest because various studies have indicated that hyaluronan-rich PDAC is correlated with the progressive properties of cancer cells, both in experimental and clinical settings. Hence, the reduction of hyaluronan in cancer tissue may represent a novel therapeutic approach for PDAC. 4-methylumbelliferone (4-MU) is a derivative of coumarin that was reported to suppress the synthesis of hyaluronan in cultured human skin fibroblasts in 1995. As an additional study, our group firstly reported that 4-MU reduced the hyaluronan synthesis of mouse melanoma cells and exerted anti-cancer activity. Subsequently, we have showed that 4-MU inhibited liver metastasis in mice inoculated with human pancreatic cancer cells. Thereafter, 4-MU has been accepted as an effective agent for hyaluronan research and is expected to have clinical applications. This review provides an overview of the interaction between PDAC and hyaluronan, the properties of 4-MU as a suppressor of the synthesis of hyaluronan, and the perspectives of PDAC treatment targeting hyaluronan.

Hyaluronan as a therapeutic target in human diseases.
            (Liang et al., 2016) Download
Accumulation and turnover of extracellular matrix is a hallmark of tissue injury, repair and remodeling in human diseases. Hyaluronan is a major component of the extracellular matrix and plays an important role in regulating tissue injury and repair, and controlling disease outcomes. The function of hyaluronan depends on its size, location, and interactions with binding partners. While fragmented hyaluronan stimulates the expression of an array of genes by a variety of cell types regulating inflammatory responses and tissue repair, cell surface hyaluronan provides protection against tissue damage from the environment and promotes regeneration and repair. The interactions of hyaluronan and its binding proteins participate in the pathogenesis of many human diseases. Thus, targeting hyaluronan and its interactions with cells and proteins may provide new approaches to developing therapeutics for inflammatory and fibrosing diseases. This review focuses on the role of hyaluronan in biological and pathological processes, and as a potential therapeutic target in human diseases.

Targeting hyaluronic acid family for cancer chemoprevention and therapy.
            (Lokeshwar et al., 2014) Download
Hyaluronic acid or hyaluronan (HA) is perhaps one of the most uncomplicated large polymers that regulates several normal physiological processes and, at the same time, contributes to the manifestation of a variety of chronic and acute diseases, including cancer. Members of the HA signaling pathway (HA synthases, HA receptors, and HYAL-1 hyaluronidase) have been experimentally shown to promote tumor growth, metastasis, and angiogenesis, and hence each of them is a potential target for cancer therapy. Furthermore, as these members are also overexpressed in a variety of carcinomas, targeting of the HA family is clinically relevant. A variety of targeted approaches have been developed to target various HA family members, including small-molecule inhibitors and antibody and vaccine therapies. These treatment approaches inhibit HA-mediated intracellular signaling that promotes tumor cell proliferation, motility, and invasion, as well as induction of endothelial cell functions. Being nontoxic, nonimmunogenic, and versatile for modifications, HA has been used in nanoparticle preparations for the targeted delivery of chemotherapy drugs and other anticancer compounds to tumor cells through interaction with cell-surface HA receptors. This review discusses basic and clinical translational aspects of targeting each HA family member and respective treatment approaches that have been described in the literature.

Hyaluronan - a functional and structural sweet spot in the tissue microenvironment.
            (Monslow et al., 2015) Download
Transition from homeostatic to reactive matrix remodeling is a fundamental adaptive tissue response to injury, inflammatory disease, fibrosis, and cancer. Alterations in architecture, physical properties, and matrix composition result in changes in biomechanical and biochemical cellular signaling. The dynamics of pericellular and extracellular matrices, including matrix protein, proteoglycan, and glycosaminoglycan modification are continually emerging as essential regulatory mechanisms underlying cellular and tissue function. Nevertheless, the impact of matrix organization on inflammation and immunity in particular and the consequent effects on tissue healing and disease outcome are arguably under-studied aspects of adaptive stress responses. Herein, we review how the predominant glycosaminoglycan hyaluronan (HA) contributes to the structure and function of the tissue microenvironment. Specifically, we examine the evidence of HA degradation and the generation of biologically active smaller HA fragments in pathological settings in vivo. We discuss how HA fragments versus nascent HA via alternate receptor-mediated signaling influence inflammatory cell recruitment and differentiation, resident cell activation, as well as tumor growth, survival, and metastasis. Finally, we discuss how HA fragmentation impacts restoration of normal tissue function and pathological outcomes in disease.

Cancer microenvironment and inflammation: role of hyaluronan.
            (Nikitovic et al., 2015) Download
The role of inflammation in the development of cancer was described as early as the nineteenth century. Abundant evidence supports the preposition that various cancers are triggered by infection and chronic inflammatory disease whereas, evading immune destruction has been proposed as one of the new "hallmarks of cancer." Changes of the tumor microenvironment have been closely correlated to cancer-mediated inflammation. Hyaluronan (HA), an important extracellular matrices component, has become recognized as an active participant in inflammatory, angiogenic, fibrotic, and cancer promoting processes. This review discusses how HA and specific HA-binding proteins participate in and regulate cancer-related inflammatory processes.

Hyaluronan, Inflammation, and Breast Cancer Progression.
            (Schwertfeger et al., 2015) Download
Breast cancer-induced inflammation in the tumor reactive stroma supports invasion and malignant progression and is contributed to by a variety of host cells including macrophages and fibroblasts. Inflammation appears to be initiated by tumor cells and surrounding host fibroblasts that secrete pro-inflammatory cytokines and chemokines and remodel the extracellular matrix (ECM) to create a pro-inflammatory "cancerized" or tumor reactive microenvironment that supports tumor expansion and invasion. The tissue polysaccharide hyaluronan (HA) is an example of an ECM component within the cancerized microenvironment that promotes breast cancer progression. Like many ECM molecules, the function of native high-molecular weight HA is altered by fragmentation, which is promoted by oxygen/nitrogen free radicals and release of hyaluronidases within the tumor microenvironment. HA fragments are pro-inflammatory and activate signaling pathways that promote survival, migration, and invasion within both tumor and host cells through binding to HA receptors such as CD44 and RHAMM/HMMR. In breast cancer, elevated HA in the peri-tumor stroma and increased HA receptor expression are prognostic for poor outcome and are associated with disease recurrence. This review addresses the critical issues regarding tumor-induced inflammation and its role in breast cancer progression focusing specifically on the changes in HA metabolism within tumor reactive stroma as a key factor in malignant progression.

Breaching the Castle Walls: Hyaluronan Depletion as a Therapeutic Approach to Cancer Therapy.
            (Shepard, 2015) Download
Hyaluronan (HA) has many functions in the extracellular milieu of normal and diseased tissues. Disease-associated HA accumulation has been shown to predict a worsened prognosis in cancer patients, with tumors having a high-extracellular HA content (HA-high) being more aggressive than their HA-low counterparts. HA-high tumor aggressiveness is derived from the specialized biomechanical and molecular properties of the HA-based assembly of HA binding proteins and the growth-promoting factors that accumulate in it. Biophysical characteristics of an HA-high tumor microenvironment include high tumor interstitial pressure, compression of tumor vasculature, and resulting tumor hypoxia. Within the tumor cell membrane, HA receptors, primarily CD44 and RHAMM, anchor the HA-high extracellular network. HA-CD44 association on the tumor cell surface enhances receptor tyrosine kinase activity to drive tumor progression and treatment resistance. Together, malignant cells in this HA-high matrix may evolve dependency on it for growth. This yields the hypothesis that depleting HA in HA-high tumors may be associated with a therapeutic benefit. A pegylated form of recombinant human hyaluronidase PH20 (PEGPH20) has been deployed as a potential cancer therapeutic in HA-high tumors. PEGPH20 can collapse this matrix by degrading the HA-assembled tumor extracellular framework, leading to tumor growth inhibition, preferentially in HA-high tumors. Enzymatic depletion of HA by PEGPH20 results in re-expansion of the tumor vasculature, reduction in tumor hypoxia, and increased penetration of therapeutic molecules into the tumor. Finally, HA-depletion results in reduced signaling via CD44/RHAMM. Taken together, HA-depletion strategies accomplish their antitumor effects by multiple mechanisms that include targeting both biophysical and molecular signaling pathways. Ongoing clinical trials are examining the potential of PEGPH20 in combination with partner therapeutics in several cancers.

Hyaluronan and hyaluronidase in genitourinary tumors.
            (Simpson and Lokeshwar, 2008) Download
Genitourinary cancers are the most frequently diagnosed cancers in men and the fifth most common in women. Management of disease through accurate and cost effective early diagnostic markers, as well as identification of valid prognostic indicators, has contributed significantly to improved treatment outcomes. In this review, we will discuss the function, regulation and clinical utility of hyaluronan (HA), genes encoding its metabolic enzymes and receptors that mediate its cellular effects. Specific HA synthase (HAS) and hyaluronidase (HAase) genes encode the enzymes that produce HA polymers and oligosaccharides, respectively. Differential effects of these enzymes in progression of genitourinary tumors are determined by the relative balance between HAS and HAase levels, as well as the distribution of receptors. The genes are regulated in a complex fashion at the transcriptional and post-translational levels, but also by epigenetic events, alternative mRNA splicing, and subcellular localization. Importantly, the major tumor-derived HAase enzyme, HYAL-1, either alone or together with HA, is an accurate diagnostic and prognostic marker for genitourinary tumors.

Hyaluronan metabolism: a major paradox in cancer biology.
            (Stern, 2005) Download
Paradoxically, both hyaluronan (HA) and hyaluronidases, the enzymes that eliminate HA, can correlate with cancer progression. Levels of HA on the surface of tumor cells are indicators of poor outcome. Certain hyaluronidases, products of tumor suppressor genes eliminated in the course of tumor spread, are used clinically in anti-cancer chemotherapy regimens. Such information would indicate that cancer progression is inhibited by hyaluronidase. Yet progression of certain cancers correlates with levels of hyaluronidase activity. An attempt is made here to understand such apparent contradictions by examining details of HA metabolism. Anabolic and catabolic pathways are comprised of the HA synthases and hyaluronidases, respectively. There are several enzymes that synthesize HA, each under a different control mechanism, generating products of differing polymer size. The hyaluronidases degrade HA in step-wise fashion, the polymer decreasing in size in quantum steps, each size-specific polymer having a different biological activity. Superimposed on these are the potent hyaluronidase inhibitors, about which very little is known. These components of HA metabolism are reviewed here for possible roles in supporting or suppressing malignant transformation, growth, invasion and metastatic spread of tumors. Such a systematic approach may reveal mechanisms used in the course of cancer progression, resolve some of the apparent disparities, render new prognostic markers, and provide new targets for therapeutic intervention.

Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look.
            (Whatcott et al., 2011) Download
Increased extracellular matrix (ECM) deposition is a characteristic observed in many solid tumors. Increased levels of one ECM component-namely, hyaluronan (HA)-leads to reduced elasticity of tumor tissue and increased interstitial fluid pressure. Multiple initial reports showed that the addition of hyaluronidase (HYAL) to chemotherapeutic regimens could greatly improve efficacy. Unfortunately, the bovine HYAL used in those studies was limited therapeutically by immunologic responses to treatment. Newly developed recombinant human HYAL has recently been introduced into clinical trials. In this article, we describe the role of HA in cancer, methods of targeting HA, and clinical studies performed to date, and we propose that targeting HA could now be an effective treatment option for patients with many different types of solid tumors.

Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target.
            (Yan et al., 2015) Download
UNLABELLED:  The reception and integration of the plethora of signals a cell receives from its microenvironment determines the cell's fate. CD44 functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a cofactor for growth factors and cytokines, and thus, CD44 is a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine signals and transduces signals to membrane-associated cytoskeletal proteins or to the nucleus to regulate a variety of gene expression levels related to cell-matrix adhesion, cell migration, proliferation, differentiation, and survival. Accumulating evidence indicates that CD44, especially CD44v isoforms, are cancer stem cell (CSC) markers and critical players in regulating the properties of CSCs, including self-renewal, tumor initiation, metastasis, and chemoradioresistance. Furthermore, there is ample evidence that CD44, especially CD44v isoforms, are valuable prognostic markers in various types of tumors. Therefore, therapies that target CD44 may destroy the CSC population, and this holds great promise for the cure of life-threatening cancers. However, many challenges remain to determining how best to use CD44 as a biomarker and therapeutic target. Here we summarize the current findings concerning the critical role of CD44/CD44v in the regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer. We also discuss the current challenges and future directions that may lead to the best use of CD44/CD44v for clinical applications. SIGNIFICANCE:  Mounting evidence indicates that cancer stem cells (CSCs) are mainly responsible for cancer aggressiveness, drug resistance, and tumor relapse. CD44, especially CD44v isoforms, have been identified as CSC surface markers for isolating and enriching CSCs in different types of cancers. The current findings concerning the critical role of CD44/CD44v in regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer are summarized. The current challenges and future directions that may lead to best use of CD44/CD44v for clinical applications are also discussed.



Kudo, D, A Suto, and K Hakamada (2017), ‘The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma.’, Int J Mol Sci, 18 (3), PubMed: 28282922
Jiang, D, J Liang, and PW Noble (2011), ‘Hyaluronan as an immune regulator in human diseases.’, Physiol Rev, 91 (1), 221-64. PubMed: 21248167
Liang, J, D Jiang, and PW Noble (2016), ‘Hyaluronan as a therapeutic target in human diseases.’, Adv Drug Deliv Rev, 97 186-203. PubMed: 26541745
Lokeshwar, VB, S Mirza, and A Jordan (2014), ‘Targeting hyaluronic acid family for cancer chemoprevention and therapy.’, Adv Cancer Res, 123 35-65. PubMed: 25081525
Monslow, J, P Govindaraju, and E Puré (2015), ‘Hyaluronan - a functional and structural sweet spot in the tissue microenvironment.’, Front Immunol, 6 231. PubMed: 26029216
Nikitovic, D, et al. (2015), ‘Cancer microenvironment and inflammation: role of hyaluronan.’, Front Immunol, 6 169. PubMed: 25926834
Schwertfeger, KL, et al. (2015), ‘Hyaluronan, Inflammation, and Breast Cancer Progression.’, Front Immunol, 6 236. PubMed: 26106384
Shepard, HM (2015), ‘Breaching the Castle Walls: Hyaluronan Depletion as a Therapeutic Approach to Cancer Therapy.’, Front Oncol, 5 192. PubMed: 26380222
Simpson, MA and VB Lokeshwar (2008), ‘Hyaluronan and hyaluronidase in genitourinary tumors.’, Front Biosci, 13 5664-80. PubMed: 18508614
Stern, R (2005), ‘Hyaluronan metabolism: a major paradox in cancer biology.’, Pathol Biol (Paris), 53 (7), 372-82. PubMed: 16085113
Whatcott, CJ, et al. (2011), ‘Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look.’, Cancer Discov, 1 (4), 291-96. PubMed: 22053288
Yan, Y, X Zuo, and D Wei (2015), ‘Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target.’, Stem Cells Transl Med, 4 (9), 1033-43. PubMed: 26136504