Lysyl-Oxidase Dependent Extracellular Matrix Stiffness in Hodgkin Lymphomas: Mechanical and Topographical Evidence
by
, , and
Massimo Alfano
1
,
Irene Locatelli
1,
Cristina D’Arrigo
2,
Marco Mora
3,
Giovanni Vozzi
4,5
,
Aurora De Acutis
5,
Roberta Pece
6, 
Sara Tavella
6,
Delfina Costa
7,
Alessandro Poggi
7,†
and
Maria Raffaella Zocchi
8,*,† 1
Division of Experimental Oncology and Unit of Urology, Urologic Research Institute, IRCCS Ospedale San Raffaele, 20132 Milan, Italy
2
Department of Electron Microscopy, Institute for Chemical Science and Technologies-National Research Council (SCITEC-CNR), 16149 Genoa, Italy
3
Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
4
Department of Information Engineering, University of Pisa, 56122 Pisa, Italy
5
Research Center E. Piaggio, University of Pisa, 56122 Pisa, Italy
6
Cellular Oncology Unit, Department of Experimental Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, 16132 Genoa, Italy
7
Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
8
Division of Immunology, Transplants and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
*
Author to whom correspondence should be addressed.
†
These authors are co-last authors.
Cancers 2022, 14(1), 259; https://doi.org/10.3390/cancers14010259
Submission received: 20 November 2021
/
Revised: 30 December 2021
/
Accepted: 3 January 2022
/
Published: 5 January 2022
(This article belongs to the Special Issue Study on Tumor Microenvironment in Lymphoma)
Simple Summary
Alterations of the composition and architecture of the extracellular matrix (ECM), leading to increased stiffness, is known to condition development, invasiveness and severity of neoplasms. In this study, we report increased lymph node (LN) stiffness in human lymphomas, measured by LN elastometry or by computerized imaging of bioptic specimens. Stiffness matched to lymphoma histotype and grading. The enzyme lysyl oxidase (LOX) is involved in the rise of collagen cross-linking in Hodgkin lymphomas, while altered architecture, shown by scanning electron microscopy and polarized light microscopy is involved in advanced follicular lymphomas. Based on these data, digital pathology may help in the staging of lymphomas, and lysyl oxidase may represent a target for therapy in Hodgkin lymphomas.
Abstract
Purpose: The biochemical composition and architecture of the extracellular matrix (ECM) is known to condition development and invasiveness of neoplasms. To clarify this point, we analyzed ECM stiffness, collagen cross-linking and anisotropy in lymph nodes (LN) of Hodgkin lymphomas (HL), follicular lymphomas (FL) and diffuse large B-cell lymphomas (DLBCL), compared with non-neoplastic LN (LDN). Methods and Results: We found increased elastic (Young’s) modulus in HL and advanced FL (grade 3A) over LDN, FL grade 1–2 and DLBCL. Digital imaging evidenced larger stromal areas in HL, where increased collagen cross-linking was found; in turn, architectural modifications were documented in FL3A by scanning electron microscopy and enhanced anisotropy by polarized light microscopy. Interestingly, HL expressed high levels of lysyl oxidase (LOX), an enzyme responsible for collagen cross-linking. Using gelatin scaffolds fabricated with a low elastic modulus, comparable to that of non-neoplastic tissues, we demonstrated that HL LN-derived mesenchymal stromal cells and HL cells increased the Young’s modulus of the extracellular microenvironment through the expression of LOX. Indeed, LOX inhibition by β-aminopropionitrile prevented the gelatin stiffness increase. Conclusions: These data indicate that different mechanical, topographical and/or architectural modifications of ECM are detectable in human lymphomas and are related to their histotype and grading.
