Deciphering Drug Resistance: Investigating the Emerging Role of Hyaluronan Metabolism and Signaling and Tumor Extracellular Matrix in Cancer Chemotherapy

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jul 27

PMID 39062846

Authors

Daiana L Vitale

Arianna Parnigoni

Manuela Viola

Evgenia Karousou

Ina Sevic

Paola Moretto

Alberto Passi

Laura Alaniz

Davide Vigetti

Affiliations

Soon will be listed here.

Abstract

Hyaluronan (HA) has gained significant attention in cancer research for its role in modulating chemoresistance. This review aims to elucidate the mechanisms by which HA contributes to chemoresistance, focusing on its interactions within the tumor microenvironment. HA is abundantly present in the extracellular matrix (ECM) and binds to cell-surface receptors such as CD44 and RHAMM. These interactions activate various signaling pathways, including PI3K/Akt, MAPK, and NF-κB, which are implicated in cell survival, proliferation, and drug resistance. HA also influences the physical properties of the tumor stroma, enhancing its density and reducing drug penetration. Additionally, HA-mediated signaling contributes to the epithelial-mesenchymal transition (EMT), a process associated with increased metastatic potential and resistance to apoptosis. Emerging therapeutic strategies aim to counteract HA-induced chemoresistance by targeting HA synthesis, degradation, metabolism, or its binding to CD44. This review underscores the complexity of HA's role in chemoresistance and highlights the potential for HA-targeted therapies to improve the efficacy of conventional chemotherapeutics.

Citing Articles

Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management.

Dong Y, Bao G Open Life Sci. 2024; 19(1):20221001.

PMID: 39655193 PMC: 11627072. DOI: 10.1515/biol-2022-1001.

References

Liu Z, Hou P, Fang J, Shao C, Shi Y, Melino G . Hyaluronic acid metabolism and chemotherapy resistance: recent advances and therapeutic potential. Mol Oncol. 2023; 18(9):2087-2106. PMC: 11467803. DOI: 10.1002/1878-0261.13551. View

Fraszczak K, Barczynski B . The Role of Cancer Stem Cell Markers in Ovarian Cancer. Cancers (Basel). 2024; 16(1). PMC: 10778113. DOI: 10.3390/cancers16010040. View

Shiina M, Bourguignon L . Selective Activation of Cancer Stem Cells by Size-Specific Hyaluronan in Head and Neck Cancer. Int J Cell Biol. 2015; 2015:989070. PMC: 4581563. DOI: 10.1155/2015/989070. View

Caon I, Bartolini B, Parnigoni A, Carava E, Moretto P, Viola M . Revisiting the hallmarks of cancer: The role of hyaluronan. Semin Cancer Biol. 2019; 62:9-19. DOI: 10.1016/j.semcancer.2019.07.007. View

Toole B, Slomiany M . Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells. Semin Cancer Biol. 2008; 18(4):244-50. PMC: 2517221. DOI: 10.1016/j.semcancer.2008.03.009. View

Locke K, Maneval D, LaBarre M . ENHANZE drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20. Drug Deliv. 2019; 26(1):98-106. PMC: 6394283. DOI: 10.1080/10717544.2018.1551442. View

Harrington B, Kamdar R, Ning F, Korrapati S, Caminear M, Hernandez L . UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer. J Exp Clin Cancer Res. 2023; 42(1):270. PMC: 10585874. DOI: 10.1186/s13046-023-02820-z. View

Liu Y, Zheng C, Huang Y, He M, Xu W, Li B . Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm (2020). 2021; 2(3):315-340. PMC: 8554658. DOI: 10.1002/mco2.55. View

Ryoo I, Choi B, Ku S, Kwak M . High CD44 expression mediates p62-associated NFE2L2/NRF2 activation in breast cancer stem cell-like cells: Implications for cancer stem cell resistance. Redox Biol. 2018; 17:246-258. PMC: 6006726. DOI: 10.1016/j.redox.2018.04.015. View

10.

Zhang G, Guo L, Yang C, Liu Y, He Y, Du Y . A novel role of breast cancer-derived hyaluronan on inducement of M2-like tumor-associated macrophages formation. Oncoimmunology. 2016; 5(6):e1172154. PMC: 4938366. DOI: 10.1080/2162402X.2016.1172154. View

11.

Hong Y, Kim Y, Kim G, Nam G, Kim S, Park Y . Degradation of tumour stromal hyaluronan by small extracellular vesicle-PH20 stimulates CD103 dendritic cells and in combination with PD-L1 blockade boosts anti-tumour immunity. J Extracell Vesicles. 2019; 8(1):1670893. PMC: 6781230. DOI: 10.1080/20013078.2019.1670893. View

12.

Sun P, Sun L, Cui J, Liu L, He Q . Long noncoding RNA HAS2-AS1 accelerates non-small cell lung cancer chemotherapy resistance by targeting LSD1/EphB3 pathway. Am J Transl Res. 2020; 12(3):950-958. PMC: 7137060. View

13.

Wang S, Bourguignon L . Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance. Am J Pathol. 2011; 178(3):956-63. PMC: 3069910. DOI: 10.1016/j.ajpath.2010.11.077. View

14.

Sawyer M, Pituskin E, Damaraju S, Bies R, Vos L, Prado C . A Uridine Glucuronosyltransferase 2B7 Polymorphism Predicts Epirubicin Clearance and Outcomes in Early-Stage Breast Cancer. Clin Breast Cancer. 2015; 16(2):139-44.e1-3. DOI: 10.1016/j.clbc.2015.09.006. View

15.

Spinelli F, Vitale D, Sevic I, Alaniz L . Hyaluronan in the Tumor Microenvironment. Adv Exp Med Biol. 2020; 1245:67-83. DOI: 10.1007/978-3-030-40146-7_3. View

16.

Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B . The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull. 2017; 7(3):339-348. PMC: 5651054. DOI: 10.15171/apb.2017.041. View

17.

Guo B, Xu X, Shao M, Yang X, He G, Qi K . UDP-glucose 6-dehydrogenase lessens sorafenib sensitivity via modulating unfolded protein response. Biochem Biophys Res Commun. 2022; 613:207-213. DOI: 10.1016/j.bbrc.2022.05.048. View

18.

Rajabi M, Mousa S . The Role of Angiogenesis in Cancer Treatment. Biomedicines. 2017; 5(2). PMC: 5489820. DOI: 10.3390/biomedicines5020034. View

19.

Zhang W, Gou P, Dupret J, Chomienne C, Rodrigues-Lima F . Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play. Transl Oncol. 2021; 14(10):101169. PMC: 8273223. DOI: 10.1016/j.tranon.2021.101169. View

20.

Fraunhoffer N, Abuelafia A, Chanez B, Bigonnet M, Gayet O, Roques J . Inhibition of glucuronidation in pancreatic cancer improves gemcitabine anticancer activity. Cancer Commun (Lond). 2022; 42(11):1212-1216. PMC: 9648386. DOI: 10.1002/cac2.12365. View