Hyaluronic Acid Modulation: Preventing Recurrence or Supporting Other Therapies – Otherwise Better Not

Recently, I was reading this article Why cancer drugs can’t take the pressure, arguing that “A major reason why cancer drugs fail is that they cannot penetrate the high-pressure environment of solid tumors.” and that the reason for that is a “naturally occurring molecule called hyaluronic acid, primarily responsible for generating elevated gel-fluid pressures in tumors.”

hyaluronic acidSo the tumor environment is surrounded by a gel, hyaluronic acid, that creates elevated fluid pressure in tumors and as the scientists suggest, this leads to an increased vessel collapse in tumors, known as a major barrier for drug delivery.

In order to reduce this vessel collapse and increase drug delivery, the researchers treated a mouse model of pancreatic cancer with a modified form of an enzyme called hyaluronidase, which breaks down hyaluronic acid. Indeed, this treatment eliminated the immobile fluid phase and allowed vessels that had collapsed under pressure to re-expand. Scientists than concluded that this approach “will be essential to designing the most appropriate and effective strategies to overcome this important and frequently underestimated resistance mechanism.” (Ref.)

After reading the article cited above I immediately remembered about reading some puzzling facts regarding hyaluronic acid action in cancer. Specifically, some are suggesting hyaluronic acid inhibition is the right way to go:

While others are suggesting hyaluronic acid is protective against cancer:

As we can see from the above references, the action of hyaluronic acid in cancer seems controversial. While I do not feel that everything is clarified about hyaluronic acid, here is a good review paper recently published on the same subject: The immunological effect of hyaluronan in tumor angiogenesis http://www.nature.com/cti/journal/v4/n12/full/cti201535a.html

Essentially, this article argues that hyaluronic acid (HA) can modulate angiogenesis and immune responses.

Based on various references, here is how I understand things:

  • hyaluronic acid is a component of the extracellular matrix dramatically increased with many disease states such as vascular disease (e.g. atherosclerosis) and cancer (Ref.)
  • in normal physiological conditions, the amount of HA is controlled by a balance between synthesis and degradation; however, HA has been shown to be abundantly accumulated in the surrounding stroma of malignant tumor
  • excessive accumulation of extracellular matrix components, including hyaluronan (HA) is common in Liver cirrhosis (Ref.)
  • is usually correlated with poor prognosis in many different cancer types, including gastric, colorectal, breast, ovarian, bladder cancer,  pancreatic, etc (Ref.)
  • there are two forms of hyaluronic acid: high-molecular weight (HMW-HA) and low-molecular weight (LMW-HA)
  • HMW-HA has anti-angiogenic properties and this is the same type of hyaluronic acid found in naked mole rat
  • on the other hand LMW-HA is pro-inflammatory (Ref.)
  • hyaluronic acid degradation products stimulate endothelial cell proliferation and migration following activation of specific hyaluronic acid receptors in particular, CD44 and Receptor for HA-Mediated Motility (Ref.) (Ref.)
  • indeed, certain environmental exposures and disease states have been shown to lead to breaking-down of HMW-HA into fragments (LMW-HA) that can stimulate expression of proinflammatory cytokines, chemokines, and growth factors (Ref.)
  • on this line if is to work against hyaluronic acid we better inhibit its sysnthesys instead of stimulating its degradation as some current clinical trials are doing using enzymes such as hyaluronidase. Nevertheless, clinical trials shown positive results even when using hyaluronidase intravenous administration before chemotheraphies in humans (Ref.)
  • three different therapeutic approaches may be identified to target HA: (1) inhibiting HA synthesis, (2) blocking HA signaling, and (3) depleting stromal HA improve chemosensitivity (Ref.)
  • HA is synthesized in mammals via the expression of three related hyaluronan synthases, HAS1, HAS2, and HAS3 – so we can also try to inhibit these to reduce HA production – Corticosteroids can inhibit the synthesis of HA by HAS (Ref.) 4-methylumbelliferone (MU) is also an inhibitor of HAS (Ref.)
  • HAS2, is the enzyme responsible for the synthesis of high-molecular weightHA ( In general, HAS3 synthesized the shortest HA polymer sizes, while HAS1 and HAS2 synthesized larger polymers, although the major population of HA produced by HAS2 tended to be concentrated on the longer end of the spectrum compared to HAS1, which generated a wider range of HA polymers) (Ref.)
  • therefore, it is better to inhibit HAS3 and if possible HAS1 (some argue that HAS1 is more relevant than expected) (Ref.)


Based on the above and a lot of other references, my conclusion is the following:

  • inhibiting the production of HA may lead to
    • prevention of recurrence (as no LMW-HA will be produced)
    • inhibition of metastasis
    • higher penetration of the chemo or other therapies in to the tumor
    • lower inflammation
    • faster growth of the existing tumors
  • breakdown of (already existing) HA may lead to
    • higher penetration of the chemo or other therapies in to the tumor
    • chance of metastasis (due to the breakdown of HA is small fragments)
  • not doing anything about HA
    • potentially slower tumor growth due to less good vessels
    • lower penetration of the chemo or other therapies in to the tumor
  • increasing HA production may lead to
    • assuming we increase HMW-HA and not LMW-HA
      • will have anti-angiogenic role possibly leading to tumor death
      • prevention of recurrence (as only HMW-HA will be produced)
    • if tumor is there
      • there is an increased risk of metastasis (due to the breakdown of HA is small fragments) – if tumor is not there and it is used preventive than no expected negatives
      • lower penetration of the chemo or other therapies in to the tumor

Consequently, I would modulate HA only in the following cases

  • as a preventive approach for e.g. recurrence both HA inhibition strategy or HMW-HA production strategy will help
  • as a chemo preparation technique to increase effectiveness or even enable effectiveness of chemo or other therapies, prior to chemo (or any other effective treatment) in order to enhance chemo penetration in the tumor

If the tumor is already develop and there is no intention to administrate chemo or any other effective treatments, I would strongly reconsider the administration of drugs modulating HA since there is a risk for triggering faster progression and/or metastasis. If I would anyway want to start something on this direction in an advance cancer case (to e.g. prevent metastasis even at the risk of faster growth of the existing tumor) I would only consider HA synthesis inhibition strategies (i.e. not HA breakdown).

Hyaluronic Acid Modulation

HA synthesis may be inhibited with the following elements:

Corticosteroids inhibit HAS2, the enzyme responsible for the synthesis of high-molecular weightHA (Ref.). In early stages this would probably not be the right enzyme to reduce HA since it is responsible for the production of the HMW-HA, which is the right form of HA that has anti-angiogenic properties. In advanced stages, any form of HA will be dangerous as HMW-HA may also be broken down in fragments and lead to metastasis. Therefore, in order to reduce any form of HA corticosteroids may be suitable for advanced cancers. Offcourse there are other reason why corticosteroids not be suitable as anti cancer treatments as some corticosteroids are known to suppress immune system.

4-Methylumbelliferone, an orally dietary supplement, can modulate and inhibit hyaluronic acid production (Ref.1,) The synthesis of HA can be suppressed by 4-methylumbelliferone (4-MU), which depletes cells from one of the substrates necessary for its synthesis, i.e. UDP-glucuronic acid, and downregulates the transcription of two of the synthases (Ref.). 4-MU is a coumarin of vegetal origin. It has been tested in a phase II clinical trial for hepatitis B and C patients indicating that 4-MU is well tolerated. 4-MU has been shown in vitro and in vivo to be an effective inhibitor of cell proliferation, migration, angiogenesis, tumor growth and metastasis. 4MU inhibits both HAS3 and HAS2 (Ref.)

4-MU stands out as a treatment option as it is available as an over the counter drug in European countries and can be ordered via online pharmacies. This is why online patient communities started to test it at home https://www.inspire.com/groups/us-too-prostate-cancer/discussion/4-mu-dietary-supplement/?page=7#replies However, based on their reports most patients using it have experienced progression while administrating 4-MU and most not using other treatments. This supports my conclusion from above: I would take 4-MU only in conjunction with another therapy.

Stimulating HA degradation with the following elements:

Hyaluronidase Enzyme: targeting the components of the stromal compartment, in conjunction with cytotoxic agents directed against the tumor cells, is gaining traction as a potential approach for treating patients and overcoming chemoresistance. Indeed, multiple preliminary clinical studies have demonstrated increased efficacy with bovine hyaluronidase treatment in cancer patients prior to chemotheraphy administration (Ref.). Recombinant human hyaluronidase (Hylenex™) has been developed in recent years to eliminates the risk of disease transmission via contaminants found in animal derived hyaluronidase.

Hyaluronidase injections are commercialy available. (Ref.) Used to help in accelerating the absorption of other injected drugs or fluids from the blood stream. Also used to disolve hyaluronic acid fillers that have become the most popular dermal fillers that are used on a global scale in the field of aesthetic and cosmetic treatments. (Ref.)

However, note that hyaluronidase (HAase) HYAL-1 degrades hyaluronic acid (HA) into proangiogenic fragments that support tumor progression (Ref.). Therefore, hyaluronidase should be only used prior to chemo or other effective anti cancer treatments. Otherwise it doesn’t make sense to use it as there is high chance it may lead to progression.

There is a biotech company called Halozyme Therapeutics using this approach in combination with various anticancer drugs including Immunotheraphy Keytruda – currently in clinical trials.

Stimulating HA production:

Chondroitin sulfate: stimulates the synthesis of high molecular weight HA in OA FLS through up-regulation of HAS1 and HAS2. It reduces the IL-1β–enhanced transcription of HAS3 and increases the production of HA of large molecular sizes.

Chondroitin sulfate, is a substance part of the next generation GcMAF (Rerum) promoted as an anti cancer solution. Since Chondroitin sulfate triggers the production of the right HA (high molecular weight HA) this approach may increase the anti-angiogenesis that may lead to tumor death. However, the risks are that the chemo penetration will also be reduced (in case that is used) and there is a higher chance to increase metastasis due to the possible breakdown of HMW-HA into LMW-HA. Indeed, preliminary research suggests that chondroitin may cause the spread or recurrence of cancer (Ref.). In this case Rerum may be a risky one in advanced cancers while it may be a protective against recurrence.

Administration & Dose:

4-Methylumbelliferone: 400mg 3x/day.  (Ref.)


Name of the 4-Methylumbelliferone product is Hymecromone or Cantabiline and it can be found at European online pharmacies and an over the counter drug. https://www.moncoinsante.co.uk/cantabiline-400-mg-boite-de-30-comprimes.html


Inhibition of Hyaluronic Acid Synthesis Suppresses Angiogenesis in Developing Endometriotic Lesions http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152302

The present study demonstrates for the first time that targeting the synthesis of HA suppresses angiogenesis in developing endometriotic lesions. Further studies have to clarify now whether in the future this anti-angiogenic effect can be used beneficially for the treatment of endometriosis.

High and low molecular weight hyaluronic acid differentially influence macrophage activation. http://www.ncbi.nlm.nih.gov/pubmed/26280020

Regardless of initial polarization state, low molecular weight hyaluronic acid induced a classically activated-like state, confirmed by up-regulation of pro-inflammatory genes, including nos2, tnf, il12b, and cd80, and enhanced secretion of nitric oxide and TNF-α. High molecular weight hyaluronic acid promoted an alternatively activated-like state, confirmed by up regulation of pro-resolving gene transcription, including arg1,il10, and mrc1, and enhanced arginase activity.

Targeting Hyaluronic Acid Family for Cancer Chemoprevention and Therapy http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791948/

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.

4-Methylumbelliferone Treatment and Hyaluronan Inhibition as a Therapeutic Strategy in Inflammation, Autoimmunity, and Cancer http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369655/

Hyaluronan (HA) is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies. Recent publications have demonstrated that when HA synthesis is inhibited using 4-methylumbelliferone (4-MU), beneficial effects are observed in several animal models of these diseases. Notably, 4-MU is an already approved drug in Europe and Asia called “hymecromone” where it is used to treat biliary spasm. However, there is uncertainty regarding how 4-MU treatment provides benefit in these animal models and the potential long-term consequences of HA inhibition. Here, we review what is known about how HA contributes to immune dysregulation and tumor progression. Then, we review what is known about 4-MU and hymecromone in terms of mechanism of action, pharmacokinetics, and safety. Finally, we review recent studies detailing the use of 4-MU to treat animal models of cancer and autoimmunity.

Sylvester Researchers Report Prevention of Lethal Prostate Cancer with 4-MU Dietary Supplement http://med.miami.edu/news/sylvester-researchers-report-prevention-of-lethal-prostate-cancer-with-4-mu

Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo http://onlinelibrary.wiley.com/doi/10.1002/ijc.26014/full

Hyaluronan (HA) has been shown to play crucial roles in the tumorigenicity of malignant tumors. Previous studies demonstrated that inhibition of HA suppressed the tumorigenicity of various malignant tumors including breast cancer. 4-methylumbelliferone (MU) has been reported to inhibit HA synthesis in several cell types. However, few studies have focused on the effects of HA inhibition in breast cancer cells by MU, nor the effects on bone metastasis. We hypothesized that MU would suppress the progression of bone metastasis viainhibition of HA synthesis. Here, we investigated the effects of MU on HA expression in MDA-MB-231 breast cancer cell line in addition to their tumorigenicity in vitro and in vivo. HAS2 mRNA expression was downregulated after 6 and 24 hr treatment with MU. Quantitative analysis of HA revealed that MU significantly inhibited the intracellular and cell surface HA. MU significantly inhibited cell growth and induced apoptosis as determined by cell proliferation and TUNEL assays, respectively. Phosphorylation of Akt was suppressed after 12 and 24 hr treatment with MU. MU treatment also inhibited cell motility as well as cell invasiveness. MU also inhibited cell growth and motility in murine fibroblast cell line NIH3T3. In vivo, administration of MU inhibited the expansion of osteolytic lesions on soft X-rays in mouse breast cancer xenograft models. HA accumulation in bone metastatic lesions was perturbed peripherally. These data suggest that MU might be a therapeutic candidate for bone metastasis of breast cancer via suppression of HA synthesis and accumulation.

Dietary Supplement 4-Methylumbelliferone: An Effective Chemopreventive and Therapeutic Agent for Prostate Cancer https://www.researchgate.net/publication/274966404_Dietary_Supplement_4-Methylumbelliferone_An_Effective_Chemopreventive_and_Therapeutic_Agent_for_Prostate_Cancer

Prevention and treatment of advanced prostate cancer (PCa) by a nontoxic agent can improve outcome, while maintaining quality of life. 4-methylumbelliferone (4-MU) is a dietary supplement that inhibits hyaluronic acid (HA) synthesis. We evaluated the chemopreventive and therapeutic efficacy and mechanism of action of 4-MU.
TRAMP mice (7-28 per group) were gavaged with 4-MU (450mg/kg/day) in a stage-specific treatment design (8-28, 12-28, 22-28 weeks). Efficacy of 4-MU (200-450mg/kg/day) was also evaluated in the PC3-ML/Luc(+) intracardiac injection and DU145 subcutaneous models. PCa cells and tissues were analyzed for HA and Phosphoinositide 3-kinase (PI-3K)/Akt signaling and apoptosis effectors. HA add-back and myristoylated Akt (mAkt) overexpression studies evaluated the mechanism of action of 4-MU. Data were analyzed with one-way analysis of variance and unpaired t test or Tukey’s multiple comparison test. All statistical tests were two-sided.
While vehicle-treated transgenic adenocarcinoma of the prostate (TRAMP) mice developed prostate tumors and metastases at 28 weeks, both were abrogated in treatment groups, without serum/organ toxicity or weight loss; no tumors developed at one year, even after stopping the treatment at 28 weeks. 4-MU did not alter the transgene or neuroendocrine marker expression but downregulated HA levels. However, 4-MU decreased microvessel density and proliferative index (P < .0001,). 4-MU completely prevented/inhibited skeletal metastasis in the PC3-ML/Luc(+) model and DU145-tumor growth (85-90% inhibition, P = .002). 4-MU also statistically significantly downregulated HA receptors, PI-3K/CD44 complex and activity, Akt signaling, and β-catenin levels/activation, but upregulated GSK-3 function, E-cadherin, and apoptosis effectors (P < .001); HA addition or mAkt overexpression rescued these effects.
4-MU is an effective nontoxic, oral chemopreventive, and therapeutic agent that targets PCa development, growth, and metastasis by abrogating HA signaling.

4-Methylumbelliferone Inhibits Angiogenesis in Vitro and in Vivo http://pubs.acs.org/doi/abs/10.1021/jf303062h?src=recsys&journalCode=jafcau

4-Methylumbelliferone (4-MU) is a hyaluronic acid biosynthesis inhibitor with antitumoral and antimetastatic effects. The objective of the present study was to determine the potential of 4-MU as an antiangiogenic compound. To fulfill this aim, cultured endothelial cells were used to perform an array of in vitro assays, as well as two different in vivo angiogenesis assays. This study demonstrates that, in fact, 4-MU behaves as a new inhibitor of both in vitro and in vivo angiogenesis. In vitro, 4-MU affects several key steps of angiogenesis, including endothelial cell proliferation, adhesion, tube formation, and extracellular matrix remodeling. Half-maximal inhibitory concentrations (IC50) values in the proliferation assay were 0.65 ± 0.04 and 0.37 ± 0.03 mM for HMEC and RF-24 endothelial cells, respectively. 4-MU (2 mM) treatment for 24 h induced apoptosis in 13% of HMEC and 5% of RF-24 cells. The number of adherent endothelial cells decreased by >20% after 24 h of treatment with 1 mM 4-MU. Minimal inhibitory concentrations in the tube formation assay were 2 and 0.5 mM 4-MU for HMEC and RF-24, respectively. Matrix metalloproteinase-2 expression was differentially altered upon 4-MU treatment in both tested endothelial cell lines. Taken together, the results suggest that 4-MU may have potential as a new candidate multitargeted bioactive compound for antiangiogenic therapy.

Targeting hyaluronan for the treatment of pancreatic ductal adenocarcinoma http://www.sciencedirect.com/science/article/pii/S2211383515300502

Progression of cancer is often associated with interactions between cancer cells and extracellular matrix (ECM) surrounding them. Increasing evidence has suggested that accumulation of hyaluronan (HA), a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized typically by a dense desmoplastic stroma with a large amount of HA, making this molecule as an attractive target for therapy. Several studies have shown efficacy of inhibitors of HA synthesis or signaling for the treatment of PDAC. Recent studies have also demonstrated substantial improvements in the effects of chemotherapy by a targeted depletion of stromal HA in PDAC using an enzymatic agent. Thus, targeting HA has been recognized as a promising therapeutic strategy to treat this highly aggressive neoplasm. In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA.


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