Crosstalk between tumor cells and lymphocytes modulates heparanase expression

• Published in: Journal of translational medicine Vol. 17; no. 1; pp. 103 - 14
• Main Authors: Theodoro, Thérèse Rachell, Matos, Leandro Luongo, Cavalheiro, Renan Pelluzzi, Justo, Giselle Zenker, Nader, Helena Bonciani, Pinhal, Maria Aparecida Silva
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 29.03.2019; BioMed Central; BMC
• Subjects: Angiogenesis; Antibodies; Biosynthesis; Bone marrow; Breast cancer; Breast neoplasms; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer cells; Cancer metastasis; Cancer therapies; Cell adhesion & migration; Cell Communication - drug effects; Cell Communication - physiology; Cell culture; Cell growth; Cells, Cultured; Coculture Techniques; Culture Media, Conditioned - pharmacology; Exosomes; Extracellular matrix; Female; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Glucuronidase - genetics; Glucuronidase - metabolism; Growth factors; Health aspects; Heparan sulfate; Heparitin Sulfate - metabolism; Heparitin Sulfate - physiology; HPSE; HPSE2; Humans; Immunocytochemistry; Lymphocyte Activation - genetics; Lymphocytes; Lymphocytes - metabolism; Lymphocytes - physiology; MCF-7 Cells; Messenger RNA; Metastases; Metastasis; Oligosaccharides; Polymerase chain reaction; Proteoglycans; Receptor Cross-Talk - drug effects; Receptor Cross-Talk - immunology; Risk factors; RNA; Stem cells; Sulfates; Tumor cells; Tumor microenvironment; Tumors; Women's health; California; Heparan sulfate; Breast neoplasms; Proteoglycans; HPSE; HPSE2; Tumor microenvironment
• DOI: 10.1186/s12967-019-1853-z
• ISSN: 1479-5876

Heparanase (HPSE) is an endo-beta-glucuronidase that degrades heparan sulfate (HS) chains on proteoglycans. The oligosaccharides generated by HPSE promote angiogenesis, tumor growth and metastasis. Heparanase-2 (HPSE2), a close homolog of HPSE, does not exhibit catalytic activity. Previous studies have demonstrated that serum or plasma from breast cancer patients showed increased expression of both heparanases in circulating lymphocytes. The aim of this study was to better understand the mechanisms involved in the upregulation of heparanases in circulating lymphocytes. Lymphocytes collected from healthy women were incubated in the presence of MCF-7 breast cancer cells (co-culture) to stimulate HPSE and HPSE2 overexpression. The protein level of heparanases was evaluated by immunocytochemistry, while mRNA expression was determined by quantitative RT-PCR. The medium obtained from co-culture of MCF-7 cells and circulating lymphocytes stimulated the expression of HPSE and HPSE2. Previous treatment of the co-culture medium with an anti-heparan sulfate proteoglycan antibody or heparitinase II inhibited the upregulation of heparanases in circulating lymphocytes. The addition of exogenous heparan sulfate (HS) enhanced the expression of both heparanases. Moreover, the co-cultured cells, as well as MCF-7 cells, secreted a higher number of exosomes expressing an increased level of HS compared to that of the exosomes secreted by circulating lymphocytes from women who were not affected by cancer. The results revealed that HS is likely responsible for mediating the expression of heparanases in circulating lymphocytes. HS secreted by tumor cells might be carried by exosome particles, confirming the key role of tumor cells, as well as secreted HS, in upregulating the expression of heparanases, suggesting a possible mechanism of crosstalk between tumor cells and circulating lymphocytes.