RESUMO
The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines.In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor.From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients.
Assuntos
Bortezomib/farmacologia , Quimiocina CCL27/metabolismo , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Receptor Cross-Talk/efeitos dos fármacos , Receptores CCR10/metabolismo , Transdução de Sinais/efeitos dos fármacos , Idoso , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Interferência de RNA , Receptores CCR10/genética , Receptores de Interleucina-10/genética , Receptores de Interleucina-10/metabolismo , Transfecção , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Chemokines are involved in almost all aspects of tumour establishment and progression. OBJECTIVE: This review gives an insight into the complexity of chemokines and chemokine signalling in tumours, especially focusing on the tuning of the immune system within the tumour microenvironment. METHODS: Experimental evidence from manipulation of the chemokine network in murine models and in vitro data are critically discussed, and the current status and potential future interventions therapeutically targeting chemokines for efficient and long-lasting tumour control in cancer patients are described.
