title: Dacarbazine promotes stromal remodeling and lymphocyte infiltration in cutaneous melanoma lesions.
abstract: 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.
authors.affiliation: Singapore Immunology Network (SIgN), ASTAR, Singapore, Singapore. alessandra_nardin@immunol.a-star.edu.sg
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nardin
authors.forename: Wing-Cheong
authors.initials: WC
authors.lastname: Wong
authors.forename: Charlene
authors.initials: C
authors.lastname: Tow
authors.forename: Thierry Jo
authors.initials: TJ
authors.lastname: Molina
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Anne
authors.initials: A
authors.lastname: Audebourg
authors.forename: Marylene
authors.initials: M
authors.lastname: Garcette
authors.forename: Anne
authors.initials: A
authors.lastname: Caignard
authors.forename: Marie-Francoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Abastado
authors.forename: Armelle
authors.initials: A
authors.lastname: Prévost-Blondel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001706:Biopsy; D003606:Dacarbazine / Q000494:pharmacology*; D018450:Disease Progression; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D053208:Kaplan-Meier Estimate; D008214:Lymphocytes / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects* / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects*; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015676:Osteonectin; D003606:Dacarbazine