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001-es BibID:	BIBFORM002762
035-os BibID:	(scopus)35448969823 (wos)000251600200021
Első szerző:	Pályiné Krekk Zsuzsanna (molekuláris biológus)
Cím:	Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer / Palyi-Krekk Z., Barok M., Isola J., Tammi M., Szollosi J., Nagy P.
Dátum:	2007
Megjegyzések:	Although trastuzumab, a recombinant humanised anti-ErbB2 antibody, is widely used in the treatment of breast cancer, neither its mechanism of action, nor the factors leading to resistance are fully understood. We have previously shown that antibody-dependent cellular cytotoxicity is pivotal in the in vivo effect of trastuzumab against JIMT-1, a cell line showing in vitro resistance to the antibody, and suggested that masking of the trastuzumab-binding epitope by MUC-4, a cell surface mucin, took place. Here, we further explored the role of masking of ErbB2 in connection with CD44 expression and synthesis of its ligand, hyaluronan. We show that high expression of CD44 observed in JIMT-1 cells correlates with ErbB2 downregulation in vivo, while siRNA-mediated inhibition of CD44 expression leads to decreased rate of trastuzumab internalisation and low cell proliferation in vitro. An inhibitor of hyaluronan synthesis, 4-methylumbelliferon (4-MU) significantly reduced the hyaluronan level of JIMT-1 cells both in vivo and in vitro leading to enhanced binding of trastuzumab to ErbB2 and increased ErbB2 down-regulation. Furthermore, the inhibitory effect of trastuzumab on the growth of JIMT-1 xenografts was significantly increased by 4-MU treatment. Our results point to the importance of the CD44-hyaluronan pathway in the escape of tumour cells from receptor-oriented therapy
Tárgyszavak:	Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Antibodies Biophysics Cell Line Cell Proliferation Cells Down-Regulation Hungary In Vitro therapy
Megjelenés:	European Journal of Cancer. - 43 : 16 (2007), p. 2423-2433. -
További szerzők:	Barok Márk (1976-) (biofizikus) Isola, Jorma Tammi, Markku (kutatóorvos) Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
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001-es BibID:	BIBFORM036695
Első szerző:	Váradi Tímea (okleveles vegyész)
Cím:	Binding of Trastuzumab to ErbB2 Is Inhibited by a High Pericellular Density of Hyaluronan / Tímea Váradi, Tamás Mersich, Päivi Auvinen, Raija Tammi, Markku Tammi, Ferenc Salamon, István Besznyák, Ferenc Jakab, Zsolt Baranyai, János Szöllősi, Peter Nagy
Dátum:	2012
Megjegyzések:	Although trastuzumab is an efficient drug, primary and acquired resistance is a challenging problem. The authors have previously shown in mouse xenograft experiments that masking ErbB2 by hyaluronan leads to diminished binding ofthe antibody and consequent resistance. In the current work, they correlated trastuzumab binding with the pericellular density of hyaluronan in ErbB2-overexpressing human breast cancer samples. A method for quantifying the relative binding of trastuzumab was developed involving constant and low-frequency background subtraction, segmenting the image to membrane and background pixels followed by evaluation of trastuzumab fluorescence, normalized with the expression level of ErbB2, only in the membrane. The normalized binding of trastuzumab showed a negative correlation with the pericellular density of hyaluronan (r = ?0.52) with the effect being the most pronounced in the extreme cases (i.e., low and high hyaluronan densities predicted strong and weak binding of trastuzumab, respectively). Removal of hyaluronan by hyaluronidase digestion unmasked the trastuzumab binding epitope of ErbB2 demonstrated by a significantly increasednormalized binding of the antibody. The results show that the accumulation of pericellular hyaluronan plays a rucial role in masking ErbB2.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban breast cancer ErbB2 trastuzumab resistance hyaluronan epitope masking Molekuláris Medicina
Megjelenés:	Journal of Histochemistry & Cytochemistry 60 : 8 (2012), p. 567-575. -
További szerzők:	Mersich Tamás (sebész) Auvinen, Paivi (kutatóorvos) Tammi, Raija (kutatóorvos) Tammi, Markku (kutatóorvos) Salamon Ferenc (1965-) Besznyák István (1980-) (sebész) Jr. Jakab Ferenc Baranyai Zsolt (sebész) Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
Pályázati támogatás:	TÁMOP-4.2.1/B-09/1/KONV-2010-0007 TÁMOP Sejt biofizika TÁMOP-4.2.2-08/1-2008-0019 TÁMOP TÁMOP-4.2.2/B-10/1-2010-0024 TÁMOP
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