Dacarbazine Promotes Stromal Remodeling and Lymphocyte Infiltration in Cutaneous Melanoma Lesions

• Published in: Journal of investigative dermatology Vol. 131; no. 9; pp. 1896 - 1905
• Main Authors: Nardin, Alessandra, Wong, Wing-Cheong, Tow, Charlene, Molina, Thierry Jo, Tissier, Frédérique, Audebourg, Anne, Garcette, Marylene, Caignard, Anne, Avril, Marie-Francoise, Abastado, Jean-Pierre, Prévost-Blondel, Armelle
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2011; Nature Publishing Group; Elsevier Limited
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating - pharmacology; Biological and medical sciences; Biopsy; Dacarbazine - pharmacology; Dermatology; Disease Progression; Extracellular Matrix - drug effects; Extracellular Matrix - pathology; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; In Vitro Techniques; Kaplan-Meier Estimate; Lymphocytes - drug effects; Lymphocytes - pathology; Male; Medical sciences; Melanoma - drug therapy; Melanoma - genetics; Melanoma - mortality; Melanoma - secondary; Middle Aged; Osteonectin - genetics; Osteonectin - metabolism; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Stromal Cells - drug effects; Stromal Cells - pathology; Tumor Microenvironment - drug effects; Tumors of the skin and soft tissue. Premalignant lesions; Young Adult; Antineoplastic agent; Dacarbazine; Alkylating agent; Skin disease; Dermatology; Malignant melanoma; Malignant tumor; Lymphocyte; Cancer
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2011.128

Dacarbazine (DTIC) is the standard first-line drug for advanced stage melanoma, but it induces objective clinical responses in only 15% of patients. This study was designed to identify molecular changes specifically induced by treatment in chemo-sensitive lesions. Using global transcriptome analysis and immunohistochemistry, we analyzed cutaneous metastases resected from patients with melanoma before and after DTIC treatment. The treatment induced similar functional changes in different lesions from the same patient. Stromal and immune response-related genes were the most frequently upregulated, particularly in lesions that responded to treatment by stabilizing or regressing. T-cell infiltration and enhanced major histocompatibility complex class II expression were observed in a subset of patients. Stable, chemo-sensitive lesions exhibited activation of genetic programs related to extracellular matrix remodeling, including increased expression of secreted protein acidic and rich in cysteine (SPARC) by tumor cells. These events were associated with local response to treatment and with superior survival in our group of patients. In contrast, SPARC expression was downregulated in lesions resistant to DTIC. Thus, chemotherapy drugs originally selected for their direct cytotoxicity to tumor cells may also influence disease progression by inducing changes in the tumor microenvironment.