Tumor Microenvironment Remodeling by 4-Methylumbelliferone Boosts the Antitumor Effect of Combined Immunotherapy in Murine Colorectal Carcinoma

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2015 Jun 25

PMID 26105158

Citations 11

Authors

Mariana Malvicini

Esteban Fiore

Valentina Ghiaccio

Flavia Piccioni

Miguel Rizzo

Lucila Olmedo Bonadeo

Mariana Garcia

Marcelo Rodriguez

Juan Bayo

Estanislao Peixoto

Catalina Atorrasagasti

Laura Alaniz

Jorge Aquino

Pablo Matar

Guillermo Mazzolini

Affiliations

Soon will be listed here.

Abstract

We have previously demonstrated that a low dose of cyclophosphamide (Cy) combined with gene therapy of interleukin-12 (AdIL-12) has a synergistic, although limited, antitumoral effect in mice with colorectal carcinoma. The main mechanism involved in the efficacy of Cy+AdIL-12 was the induction of a specific immune response mediated by cytotoxic T lymphocytes. Our current aims were to evaluate the effects of 4-methylumbelliferone (4Mu), a selective inhibitor of hyaluronan (HA) synthesis, on tumor microenvironment (TME) and to investigate how 4Mu affects the therapeutic efficacy of Cy+AdIL-12. The results showed that 4Mu significantly reduced the amount of tumoral HA leading to a significant decrease in tumor interstitial pressure (TIP). As a consequence, tumor perfusion was improved allowing an increased adenoviral transgene expression. In addition, treatment with 4Mu boosted the number of cytotoxic T lymphocytes that reach the tumor after adoptive transfer resulting in a potent inhibition of tumor growth. Importantly, we observed complete tumor regression in 75% of mice when 4Mu was administrated in combination with Cy+AdIL-12. The triple combination 4Mu+Cy+AdIL-12 also induced a shift toward antiangiogenic factors production in tumor milieu. Our results showed that TME remodeling is an interesting strategy to increase the efficacy of anticancer immunotherapies based on gene and/or cell therapy.

Citing Articles

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Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy.

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References

Ropponen K, Tammi M, Parkkinen J, Eskelinen M, Tammi R, Lipponen P . Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res. 1998; 58(2):342-7. View

Toole B . Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004; 4(7):528-39. DOI: 10.1038/nrc1391. View

Balkwill F, Capasso M, Hagemann T . The tumor microenvironment at a glance. J Cell Sci. 2013; 125(Pt 23):5591-6. DOI: 10.1242/jcs.116392. View

Taghian A, Abi-Raad R, Assaad S, Casty A, Ancukiewicz M, Yeh E . Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. J Clin Oncol. 2005; 23(9):1951-61. DOI: 10.1200/JCO.2005.08.119. View

Heldin C, Rubin K, Pietras K, Ostman A . High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer. 2004; 4(10):806-13. DOI: 10.1038/nrc1456. View

Jain R . Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005; 307(5706):58-62. DOI: 10.1126/science.1104819. View

Ariffin A, Forde P, Jahangeer S, Soden D, Hinchion J . Releasing pressure in tumors: what do we know so far and where do we go from here? A review. Cancer Res. 2014; 74(10):2655-62. DOI: 10.1158/0008-5472.CAN-13-3696. View

Kultti A, Pasonen-Seppanen S, Jauhiainen M, Rilla K, Karna R, Pyoria E . 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp Cell Res. 2009; 315(11):1914-23. DOI: 10.1016/j.yexcr.2009.03.002. View

Miamen A, Gustafson M, Roberts L . Rethinking cancer immunotherapy: Using advanced cancer genetics in immune-mediated eradication of gastrointestinal cancers. Hepatology. 2014; 60(6):2121-4. DOI: 10.1002/hep.27442. View

10.

Cordo-Russo R, Garcia M, Barrientos G, Orsal A, Viola M, Moschansky P . Murine abortion is associated with enhanced hyaluronan expression and abnormal localization at the fetomaternal interface. Placenta. 2008; 30(1):88-95. DOI: 10.1016/j.placenta.2008.10.013. View

11.

Postow M, Chesney J, Pavlick A, Robert C, Grossmann K, McDermott D . Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015; 372(21):2006-17. PMC: 5744258. DOI: 10.1056/NEJMoa1414428. View

12.

Kalluri R . Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer. 2003; 3(6):422-33. DOI: 10.1038/nrc1094. View

13.

Takeda S, Aburada M . The choleretic mechanism of coumarin compounds and phenolic compounds. J Pharmacobiodyn. 1981; 4(9):724-34. DOI: 10.1248/bpb1978.4.724. View

14.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

15.

Padera T, Stoll B, Tooredman J, Capen D, Tomaso E, Jain R . Pathology: cancer cells compress intratumour vessels. Nature. 2004; 427(6976):695. DOI: 10.1038/427695a. View

16.

Piccioni F, Fiore E, Bayo J, Atorrasagasti C, Peixoto E, Rizzo M . 4-methylumbelliferone inhibits hepatocellular carcinoma growth by decreasing IL-6 production and angiogenesis. Glycobiology. 2015; 25(8):825-35. DOI: 10.1093/glycob/cwv023. View

17.

Poschke I, Mougiakakos D, Kiessling R . Camouflage and sabotage: tumor escape from the immune system. Cancer Immunol Immunother. 2011; 60(8):1161-71. PMC: 11028815. DOI: 10.1007/s00262-011-1012-8. View

18.

Morohashi H, Kon A, Nakai M, Yamaguchi M, Kakizaki I, Yoshihara S . Study of hyaluronan synthase inhibitor, 4-methylumbelliferone derivatives on human pancreatic cancer cell (KP1-NL). Biochem Biophys Res Commun. 2006; 345(4):1454-9. DOI: 10.1016/j.bbrc.2006.05.037. View

19.

Kakizaki I, Kojima K, Takagaki K, Endo M, Kannagi R, Ito M . A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone. J Biol Chem. 2004; 279(32):33281-9. DOI: 10.1074/jbc.M405918200. View

20.

Lokeshwar V, Lopez L, Munoz D, Chi A, Shirodkar S, Lokeshwar S . Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. Cancer Res. 2010; 70(7):2613-23. PMC: 2848908. DOI: 10.1158/0008-5472.CAN-09-3185. View