NIH Public Access Richard G. Posner Galen Hostetter , and Daniel … 2011... · Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look Clifford J

Targeting the tumor microenvironment in cancer: whyhyaluronidase deserves a second look

Clifford J. Whatcott1,*, Haiyong Han1, Richard G. Posner1, Galen Hostetter2, and Daniel VonHoff M1

1Clinical Translational Research Division, The Translational Genomics Research Institute,Phoenix, Arizona, 85004, USA2Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix,Arizona, 85004, USA

AbstractIncreased 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 oftumor tissue and increased interstitial fluid pressure. Multiple initial reports demonstrated that theaddition of hyaluronidase to chemotherapeutic regimens could significantly improve efficacy.Unfortunately, the bovine hyaluronidase used in those studies was limited therapeutically byimmunologic responses to treatment. Newly developed recombinant human hyaluronidase hasrecently been introduced into clinical trials. In this article, we describe the role of HA in cancer,methods of targeting HA, clinical studies performed to date, and propose that targeting HA couldnow be an effective treatment option for patients with many different types of solid tumors.

Keywordshyaluronidase; hyaluronan; tumor microenvironment; extracellular matrix; cancer

INTRODUCTIONMany solid tumors develop extensive fibroses, a result of what is termed the desmoplasticreaction [reviewed in 1]. Desmoplasia leads to a significant increase in the production ofextracellular matrix proteins, as well as extensive proliferation of myofibroblast-like cells.The result is the formation of a dense and fibrous connective tissue that is comprised ofmultiple extracellular matrix (ECM) components including collagen types I, III, and IV,fibronectin, laminin, hyaluronan, as well as the glycoprotein osteonectin (also known assecreted protein, acidic and rich in cysteine, or SPARC) (Figure 1). This fibroinflammatorycomponent of the tumor (sometimes called stroma) contributes to an increase in tumorinterstitial fluid pressure, blocking perfusion of anticancer therapies to the tumor cells, andcontributes generally to chemoresistance [2] (see Table 1 for individual components andtheir proposed mechanism of chemoresistance). Consequently, targeting the components ofthe stromal compartment, in conjunction with cytotoxic agents directed against the tumorcells, is gaining traction as a potential approach for treating patients and overcomingchemoresistance.

*Correspondence: 13208 E. Shea Blvd, Suite 100, Scottsdale, AZ 85259, [email protected], Phone: 602-343-8631, Fax:602-358-8360.

NIH Public AccessAuthor ManuscriptCancer Discov. Author manuscript; available in PMC 2012 September 1.

Published in final edited form as:Cancer Discov. 2011 September ; 1(4): 291–296. doi:10.1158/2159-8290.CD-11-0136.

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The concept of directing therapies towards the stromal compartment as a means to enhancedrug perfusion is supported by a recent report demonstrating that stromal depletion by nab-paclitaxel (which accumulates in tumor tissues high in SPARC) resulted in improvedgemcitabine delivery in a primary human xenograft model for pancreatic cancer [3]. Inaddition, using a genetically engineered mouse model of pancreatic cancer, Olive andcolleagues demonstrated that stromal depletion by hedgehog pathway inhibitors enhancedthe intratumor concentration of gemcitabine and resulted in significantly increased survivalof tumor bearing mice [4].

Enzymes that degrade the extracellular matrix (ECM) have also been proposed as stroma-targeting agents. However, the immunoreactivity and pH sensitivity of ECM targetingagents such as the collagenases has been a problem that has limited their study in vivo.Another ECM component that may be targeted by a degrading enzyme is hyaluronan.Hyaluronan (HA) is a linear polysaccharide comprised of glucuronic acid and N-acetylglucosamine and plays an important role in a diverse range of cellular processes(Figure 2). Elements of HA and HA metabolism are thought to be involved in biologicalfunctions related to cell proliferation, tissue hydration, cell motility, inflammation,angiogenesis, and malignancy. Hyaluronan is distributed universally in the extracellularspaces of most tissues, with especially high concentrations found within connective tissues.Unlike the other protein bound and sulfated glycosaminoglycans (GAGs), HA is a uniquepolyanionic and protein-free polysaccharide that has an exceptional ability to increaseviscosity, expand volume, and provide structural support in various locations and contextswithin the body. While steady-state levels of HA are generally quite low in most normaltissues, HA levels dramatically increase with many disease states such as vascular disease(e.g. atherosclerosis) and cancer. Furthermore, high HA levels have been correlated withpoor prognosis in many different cancer types, including gastric, colorectal, breast, ovarian,and bladder cancer. Because HA functions in ion exchange, and may also act as a molecularsieve that prevents the penetration of drugs, it is thought that treatment with agents thatdegrade HA, such as a hyaluronidase, may have the potential to increase penetration ofdrugs through the stromal compartment and ultimately into tumor cells. Given the importantrole of HA and the ECM in solid tumors, it is possible that targeting the ECM with agentssuch as hyaluronidase could prove effective in improving therapeutic outcomes in patientswith solid tumors. This has led us to consider “why aren’t we now targeting the tumorstroma with hyaluronidase in our treatment of cancer?”

HYALURONAN AND ITS ROLE IN CANCERHyaluronan is a protein-free, acetone insoluble polysaccharide first isolated from hyaloid (orvitreous) matter and reported to contain uronic acid. It is ubiquitously distributed throughoutthe human body, with particularly high concentrations seen in the skin, eyes, in cartilage,and in synovial fluid. HA’s structure gives it great capacity to interact with water molecules,resulting in a vastly increased volume, as well as increased viscosity of HA containingsolutions. These properties have also led many to infer that HA was largely an inertmolecule functioning to maintain the physical volume and rigidity of connective tissue.However, with the discovery of the HA binding proteins, or hyaladherins, it became clearthat their functional reach was much greater. The discovery of the proteoglycans, aggrecanand link protein, as well as the discovery of the HA-binding surface receptors, CD44 andRHAMM, revealed that HA is involved in the direct signaling of many biological processes,including cell proliferation, migration, adhesion, and even the recruitment of leucocytessuch as the neutrophils.

Studies of many cancer types, including pancreatic ductal adenocarcinoma (PDAC), indicatethat an accumulation of HA occurs in neoplastic tissues. Indeed, it appears that most

Whatcott et al. Page 2

Cancer Discov. Author manuscript; available in PMC 2012 September 1.

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epithelial tumors exhibit high levels of HA localizing to their peritumoral, or stromal,compartments. Interestingly, high HA levels have also been detected at the invasive front ofgrowing tumors, suggesting that HA may be involved not only in cell proliferation, butpossibly in invasion as well. Indeed, Bertrand and colleagues observed a 4.4-fold (± 0.4)increase in HA staining relative to adjacent normal tissue at the invasive edges in breasttumors, whereas only a 3.3-fold (± 0.4) increase was seen in central locations within thetumor (P<0.05) [5]. HA interaction with CD44 facilitates colon tumor cell migration, as wellas migration in other tumor models, including breast and brain cancer cells. The level of HAitself correlates with overall tumor aggressiveness and increased cell migration andproliferation in breast and ovarian cancer. Tumor cells that overexpress the hyaluronansynthase, HAS1, to varying degrees experience increased proliferation rates. While itremains to be seen whether the HAS may serve as a definitive tumor biomarker, urine HAand hyaluronidase levels may serve as suitable markers for bladder cancer, includingassessment of tumor grade. In addition, we now know that HA levels correlate withmalignancy in mesothelioma, and may serve as a potential diagnostic marker. It seems clearthat a balance of the activity of the hyaluronan synthases with hyaluronidase activity isnecessary for normal tissue function.

TARGETING HYALURONANIn normal tissues, HA levels are maintained through a balance of synthesis by hyaluronansynthase (HAS) and degradation by the enzyme hyaluronidase. HA is synthesized inmammals via the expression of three related hyaluronan synthases, HAS1, HAS2, and HAS3.Corticosteroids can inhibit the synthesis of HA by HAS. Indeed, the addition of cortisol tocultured aortic smooth muscle cells can reduce the production of HA by as much as 50%.This effect was also observed in a recent study by Gebhardt et al, wherein they report a rapiddecrease of approximately 50% of HA levels, as well as a decrease in HAS2 expression, inthe skin following topical treatment with dexamethasone [6]. Except in the treatment ofpatients with hematologic malignancies, clinical research into the addition of thecorticosteroids to anticancer therapies for patients with solid tumors has been limited (exceptto prevent nausea and vomiting).

In addition to corticosteroids, the HAS inhibitor, 4-methylumbelliferone (MU), has beendeveloped and proposed as an alternative approach to lowering HA levels. MU has beenshown to increase the efficacy of gemcitabine by inhibiting the growth of cancer cell linesover gemcitabine alone, without significant growth inhibition itself. Furthermore, Yoshiharaet al. have shown that MU decreases liver metastases in a mouse model for melanoma [7]. Inaddition, MU also reduces tumorigenicity, including reduced proliferation and motility, inesophageal squamous cell carcinoma or prostate cancer cells. MU is currently beinginvestigated in clinical trials for the treatment of patients with chronic hepatitis infection(www.clinicaltrials.gov, NCT00225537), though there are no reports to determine if theeffects of MU will enhance anticancer therapies in patients. With several very recent reportsof the efficacy of MU in breast or prostate cancer xenograft mouse models showingsignificant reduction in tumor growth, studies of MU’s efficacy in human trials are likely tobe forthcoming [8].

Altering the breakdown of HA has also been proposed as a means to target HAaccumulation. Catabolism of HA, and balance of HA levels, are mainly mediated by thehyaluronidases. Six genes have been identified that encode for the different hyaluronidases(HYALs), including HYAL1, -2, -3, -4, PHYAL1, and PH20. The HYALs catalyze thehydrolysis of HA and function as endo-β-acetyl-hexosaminidases. HYAL1 and -2 maintainthe highest enzymatic activity in mammals, turning over as much as a third of the total HAeach day. The addition of hyaluronidase to chemotherapeutics enhances the catabolism of



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http://www.clinicaltrials.gov

HA, as well as significantly increases the efficacy of the chemotherapeutics even in tumorspreviously deemed chemoresistant. The effectiveness of hyaluronidase in improvingchemotherapies has been explored in multiple tumor types including breast, brain,melanoma, and sarcoma (Table 2). The synergistic effect of adding hyaluronidase tochemotherapeutics is thought to aid in cancer treatment by reducing intratumoral pressure,or by breaking down hyaluronan’s ability to function as a molecular sieve [2]. Alternatively,the synergistic benefit may instead occur by means of a chemosensitizing effect.

In cell culture models, the addition of hyaluronidase decreases intrinsic chemoresistance inspheroid models of cancer, resulting in significantly disaggregated spheroids, increased drugpenetration, and increased cell death [9]. Using a breast cancer xenograft model, however,Beckenlehner and colleagues (1992) demonstrated an increased susceptibility to doxorubicinwhen animals were pretreated with hyaluronidase prior to doxorubicin [10]. Otherinvestigators have shown that hyaluronidase pretreatment can result in increased intratumordrug concentrations. Indeed, Muckenschabel et al., (1996) observed increases as high as 16-to 32- fold in tumor-specific melphalan concentrations in a melanoma study [11]. Mountingevidence suggests that drugs may fail due to an inability to attain significant intratumorconcentrations [2]. Thus, the finding that hyaluronidase pretreatment increased intratumordrug concentration is particularly exciting, as it may increase the efficacy of currenttherapies in patients.

CLINICAL STUDIES INCORPORATING HYALURONIDASEMultiple preliminary clinical studies have demonstrated increased efficacy with bovinehyaluronidase pretreatment in cancer patients (Table 2). Baumgartner et al (1998) havereviewed the early pilot clinical trials involving bovine hyaluronidase [12]. In a small studyof six patients the addition of intralesional bovine hyaluronidase to intralesional vinblastinetreatment was shown to be more effective at treating cutaneous lesions of Kaposi’s sarcomathan vinblastine alone and resulted in reduced recurrence [13]. This reduced recurrence wasalso seen in a study reporting on the addition of bovine hyaluronidase to standardcarboplatin and etoposide treatment for malignant brain tumors [14]. In this study, whichincluded 40 pediatric brain cancer patients, both event free survival and overall survival at36 months were significantly improved with the addition of a 30 minute infusion of bovinehyaluronidase prior to chemotherapy treatment (Table 2). Similarly, in a study looking at theeffects of mitomycin C in combination with bovine hyaluronidase administeredintravesically, recurrence in bladder cancer patients was reduced from 32% in mitomycin conly treated patients to 7% with the addition of hyaluronidase (P<0.05) [15]. In two studies,which enrolled a total of 80 patients, bovine hyaluronidase delivered intravenously wasadded to chemotherapy or chemotherapy plus radiation therapy for advanced squamous cellcarcinoma of the head and neck. In these studies, a complete response was achieved in 84%of those treated, with a 47% survival observed over five years [16]. In a study of 43 patientswith high-grade astrocytoma, it was reported that the addition of hyaluronidase did notproduce a significant improvement in tumor regression [12]. However, the authors suggestthat any synergy of hyaluronidase may have been obscured after being compared to adifferent, more effective agent later in the study. More specifically, the drug used in the firstsegment of the astrocytoma study, Lomustine (CCNU), is only slightly effective againstastrocytoma as a single agent and thus hyaluronidase did not produce a significantimprovement relative to the more effective agent used in segment two, Carmustine (BCNU)[12].

Considering these results, one might ask why hyaluronidase has not been studied more fullyor gained broader acceptance. One particular limitation of hyaluronidase as a therapeuticagent in prior studies has been the development of allergic reactions by patients to this



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enzyme due to its bovine origin. Indeed, multiple studies report that as many as 32% ofpatients harbor reactive IgE antibodies to the bovine hyaluronidase preparation, prior totherapy, inducing various reactions from urticaria, tachycardia, to shock [12]. Bovinehyaluronidase treatment has resulted in allergic reactions, even anaphylaxis. Furthermore,the development of anti-hyaluronidase antibodies following treatment limits its usefulness inany subsequent treatment, with elevated antibodies present for six weeks or more followingintravenous or intramuscular treatment.

Recombinant human hyaluronidase (Hylenex™) has been developed in recent years. Therecombinant human material eliminates the risk of disease transmission via contaminantsfound in animal derived hyaluronidase. The recombinant human material did not induceallergic reactions in a cohort of 100 volunteer subjects who were injected intradermally [17].The recombinant human molecule is now used subcutaneously, consistent with the FDAapproved label to help with dispersion and absorption of various injected drugs [17].Recombinant hyaluronidase is currently being investigated under different formulations forboth superficial bladder cancer (phase I/II, NCT00318643) where it is being used as purifiedrecombinant material and in patients with solid tumors (phase I, NCT00834704) where isbeing utilized in the pegylated form.

Considering the biological role of HA, and the many locations in which it is found, sideeffects of repeated hyaluronidase treatment as part of an anticancer regimen might induceinflammation or pain in the joints. It appears that some of the side effects of enhancedhyaluronidase activity in normal tissue observed in earlier studies, however, were controlledby the administration of corticosteroids [12]. The ongoing phase I trial used pegylatedmaterial, PEGPH20, because of the improved half life of the recombinant enzyme. In thisstudy, 50µg/kg induced grade 3 muscle/joint pain, while doses of 0.5µg/kg and 0.75µg/kg ofhyaluronidase were generally well tolerated [18]. Additional work in canine modelssuggesting amelioration of the musculoskeletal events by use of dexamethasone is alsobeing examined in the ongoing phase I trial.

Given the role of the stromal compartment in pancreatic ductal adenocarcinoma and othercancers, it is likely that targeting HA in pancreatic cancer has potential for improvingcurrent therapies [1]. With the clinical availability of recombinant hyaluronidase, there areimproved prospects for targeting HA for the treatment of cancer, particularly in cancer typesknown to be fibrotic. In a recent conference report, the authors Thompson and colleaguesobserved a 50% increase in median survival time in mice bearing pancreatic cancerxenograft tumors treated with gemcitabine plus hyaluronidase [19]. Taken together, theseresults warrant further clinical investigation of targeting HA in a variety of tumors,including pancreatic ductal adenocarcinoma, in which the stroma is thought to play a keyrole in limiting drug delivery.

CONCLUDING REMARKSWith such promising preliminary clinical results following the addition of early forms (e.g.,bovine) of hyaluronidase to chemotherapeutic treatments, we should again reconsider thepower in targeting components of the tumor microenvironment, and especially hyaluronan.Based on current and past clinical studies, future therapeutic regimens for patients withcancer may significantly benefit from agents targeting critical pathways in the development,progression, and perpetuation of the tumor stroma, particularly hyaluronan. Certainly, onemust remain cognizant of HA’s function in many other parts of the body. HA’s role insynovial fluid or the vitreous humor could become problematic following long termtreatment with hyaluronidase. However, with the development of a recombinanthyaluronidase, some of the significant limitations (i.e., immune reactions) to targeting



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hyaluronan with bovine hyaluronidase have been addressed. These developments will allowfor greater utility in studying hyaluronidase as part of an anticancer therapy regimen byyielding greater flexibility in route of administration as well as treatment schedule in clinicaltrials. Even using bovine hyaluronidase, targeting hyaluronan as part of a combinationregimen has shown promise in the clinic. Utilizing recombinant human hyaluronidase as partof an anticancer regimen is now possible. It also has one key advantage over other ECMtargeting alternatives in that it is available now. Pegylated recombinant hyaluronidase is inongoing phase I trials. Although it is likely the enzyme will cause some musculoskeletalevents, and may also present challenges in wound healing, inhibiting a key stromalcomponent such as HA with recombinant human hyaluronidase could improve the clinicaloutcomes in individuals with the most deadly types of cancer, such as pancreatic ductaladenocarcinoma. In such a disease, any potential improvement in the effective delivery oftherapeutics should be cause for serious consideration.

AcknowledgmentsWe thank Dr. Candice Nulsen for her critique and insights in the preparation of this manuscript. This work wassupported in part by a grant from Stand Up to Cancer (SU2C), and U01 and P01 grants from the NIH/NCI(CA128454, CA109552, respectively).

References1. Mahadevan D, Von Hoff DD. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol

Cancer Ther. 2007; 6:1186–1197. [PubMed: 17406031]2. Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006; 6:583–592.

[PubMed: 16862189]3. Maitra A, Rajeshkumar NV, Rudek M, Garrido-Laguna I, Laheru D, Iglesias J, et al. Abstract C246:

nab®-paclitaxel targets tumor stroma and results, combined with gemcitabine, in high efficacyagainst pancreatic cancer models. Mol Cancer Ther. 2009; 8:C246.

4. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition ofHedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.Science. 2009; 324:1457–1461. [PubMed: 19460966]

5. Bertrand P, Girard N, Delpech B, Duval C, d'Anjou J, Dauce JP. Hyaluronan (hyaluronic acid) andhyaluronectin in the extracellular matrix of human breast carcinomas: comparison between invasiveand non-invasive areas. Int J Cancer. 1992; 52:1–6. [PubMed: 1379993]

6. Gebhardt C, Averbeck M, Diedenhofen N, Willenberg A, Anderegg U, Sleeman JP, et al. Dermalhyaluronan is rapidly reduced by topical treatment with glucocorticoids. J Invest Dermatol. 2010;130:141–149. [PubMed: 19609316]

7. Yoshihara S, Kon A, Kudo D, Nakazawa H, Kakizaki I, Sasaki M, et al. A hyaluronan synthasesuppressor, 4-methylumbelliferone, inhibits liver metastasis of melanoma cells. FEBS Lett. 2005;579:2722–2726. [PubMed: 15862315]

8. Lokeshwar VB, Lopez LE, Munoz D, Chi A, Shirodkar SP, Lokeshwar SD, et al. Antitumor activityof hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. Cancer Res.2010; 70:2613–2623. [PubMed: 20332231]

9. Kohno N, Ohnuma T, Truog P. Effects of hyaluronidase on doxorubicin penetration into squamouscarcinoma multicellular tumor spheroids and its cell lethality. J Cancer Res Clin Oncol. 1994;120:293–297. [PubMed: 8126058]

10. Beckenlehner K, Bannke S, Spruss T, Bernhardt G, Schonenberg H, Schiess W. Hyaluronidaseenhances the activity of adriamycin in breast cancer models in vitro and in vivo. J Cancer Res ClinOncol. 1992; 118:591–596. [PubMed: 1517281]

11. Muckenschnabel I, Bernhardt G, Spruss T, Buschauer A. Hyaluronidase pretreatment producesselective melphalan enrichment in malignant melanoma implanted in nude mice. CancerChemother Pharmacol. 1996; 38:88–94. [PubMed: 8603457]



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12. Baumgartner G, Gomar-Hoss C, Sakr L, Ulsperger E, Wogritsch C. The impact of extracellularmatrix on the chemoresistance of solid tumors--experimental and clinical results of hyaluronidaseas additive to cytostatic chemotherapy. Cancer Lett. 1998; 131:85–99. [PubMed: 9839623]

13. Smith KJ, Skelton HG, Turiansky G, Wagner KF. Hyaluronidase enhances the therapeutic effect ofvinblastine in intralesional treatment of Kaposi's sarcoma. Military Medical Consortium for theAdvancement of Retroviral Research (MMCARR). J Am Acad Dermatol. 1997; 36:239–242.[PubMed: 9039176]

14. Pillwein K, Fuiko R, Slavc I, Czech T, Hawliczek G, Bernhardt G, et al. Hyaluronidase additionalto standard chemotherapy improves outcome for children with malignant brain tumors. CancerLett. 1998; 131:101–108. [PubMed: 9839624]

15. Maier U, Baumgartner G. Metaphylactic effect of mitomycin C with and without hyaluronidaseafter transurethral resection of bladder cancer: randomized trial. J Urol. 1989; 141:529–530.[PubMed: 2493098]

16. Klocker J, Sabitzer H, Raunik W, Wieser S, Schumer J. Hyaluronidase as additive to inductionchemotherapy in advanced squamous cell carcinoma of the head and neck. Cancer Lett. 1998;131:113–115. [PubMed: 9839626]

17. Yocum RC, Kennard D, Heiner LS. Assessment and implication of the allergic sensitivity to asingle dose of recombinant human hyaluronidase injection: a double-blind, placebo-controlledclinical trial. J Infus Nurs. 2007; 30:293–299. [PubMed: 17895809]

18. Shepard HM, Frost GI, Ryback ME, Ramanathan RK, Von Hoff DD, Infante JR, et al. Targetinghyaluronan (HA) in tumor stroma: Translational evaluation of pegylated hyaluronidase(PEGPH20, P) in animal models and patients (PTS) with advanced solid tumors. AmericanSociety for Clinical Oncology, Molecular Markers in Cancer. 2010 Abstract 114.

19. Thompson CB, Shepard HM, O'Connor PM, Kadhim S, Jiang P, Osgood RJ, et al. Enzymaticdepletion of tumor hyaluronan induces antitumor responses in preclinical animal models. MolCancer Ther. 2010; 9:3052–3064. [PubMed: 20978165]

20. Baumgartner G, Fortelny A, Zanker KS, Kroczek R. Phase I study in chemoresistant loco-regionalmalignant disease with hyaluronidase. Regional Cancer Treatment. 1988; 1:55–58.



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Figure 1.Illustration of invading epithelial tumor cells and the associated tumor microenvironment.Dissolution of the basement membrane is accompanied by the production and secretion ofnumerous extracellular matrix components, including the collagens, fibronectin, laminin,and hyaluronan, as part of the myofibroblast-mediated desmoplastic reaction. Infiltratingimmune cells also contribute to the signaling involved in the desmoplastic reaction. Theexpansion of the stromal compartment and the production of the extracellular matrixproteins are thought to result in greater intratumoral pressure and contribute to a reduction ineffective drug delivery.



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Figure 2.Chemical structure of hyaluronan. Hyaluronan is a linear polysaccharide composed ofrepeating units of glucuronic acid and N-acetylglucosamine. Hyaluronan is a nonsulfatedglycosaminoglycan and participates as an integral component of the extracellular matrix.



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Table 1

Extracellular matrix components which may contribute to chemoresistance

ECM component Functional role in chemoresistance

Collagen I, III, IV Enhances tumor cell proliferation, structural support of ECM

Decorin Binds TGF-β, tightens collagen fibrils

Hyaluronan Synergizes with collagen network, increases interstitial fluid pressure

Versican Enhances tumor cell proliferation, confers resistance to apoptosis

Fibronectin Confers resistance to apoptosis

Laminin Confers resistance to apoptosis

Osteonectin/SPARC Enhances tumor cell proliferation and metastasis


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Tabl

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Early

clin

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ls in

vest

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the

coad

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of b

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alur

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with

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py. R

efer

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2–14

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Stud

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type

Tum

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hem

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Num

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of p

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C56

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curr

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NIH Public Access Richard G. Posner Galen Hostetter , and Daniel … 2011... · Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look Clifford J