title: Tumor-associated fibroblasts promote the proliferation and decrease the doxorubicin sensitivity of liposarcoma cells.
abstract: The reasons for the distinct chemoresistance of liposarcomas and their high risk of local recurrence still remain unclear. Depending on the histological subtype of liposarcoma, first-line therapy with the cytostatic agent, doxorubicin, only achieves response rates of approximately 36%. Approximatley 70% of all local recurrences develop in spite of complete surgical resection of the primary tumor with microscopically negative margins. In this study, we aimed to assess the influence of tumor-associated fibroblasts (TAFs) obtained from surgically removed liposarcomas on the well-established human liposarcoma SW872 cell line. Intratumoral TAFs were isolated from intermediate- and high-grade liposarcoma samples. The human liposarcoma cell line, SW872, was co-cultured with the corresponding TAFs or with dermal fibroblasts as a control. The proliferation (by BrdU assay), cell viability (by MTT assay) and sensitivity to doxorubicin (using the iCELLigence system) of the co-cultured SW872 cells were examined. The SW872 cells exhibited a significant increase in proliferation and viability when co-cultured with the TAFs. As detected by real-time cell analysis, the SW872 cells co-cultured with the TAFs exhibited a diminished response towards doxorubicin. Notably, co-culture with TAFs obtained from high-grade liposarcoma samples resulted in higher proliferation and increased chemoresistance than co-culture with TAFs obtained from intermediate-grade liposarcoma samples. The findings of the present study thus indicate that TAFs from liposarcomas enhance the proliferation and decrease the chemosensitivity of SW872 liposarcoma cells significantly compared with normal fibroblasts from the dermis. TAFs from more malignant liposarcomas promoted tumor cell proliferation and chemoresistance more strikingly than TAFs from less malignant liposarcomas. These data provide evidence for the influence of the tumor microenvironment on liposarcoma and support for further investigations in patients with different liposarcoma subentities, assessing the influence of TAFs on tumor progression.
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG-University Hospital Bergmannsheil, D-44789 Bochum, Germany.
authors.forename: Kamran
authors.initials: K
authors.lastname: Harati
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG-University Hospital Bergmannsheil, D-44789 Bochum, Germany.
authors.forename: Adrien
authors.initials: A
authors.lastname: Daigeler
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG-University Hospital Bergmannsheil, D-44789 Bochum, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hirsch
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG-University Hospital Bergmannsheil, D-44789 Bochum, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jacobsen
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG-University Hospital Bergmannsheil, D-44789 Bochum, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Behr
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG-University Hospital Bergmannsheil, D-44789 Bochum, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wallner
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG-University Hospital Bergmannsheil, D-44789 Bochum, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Lehnhardt
authors.affiliation: Department of Plastic Surgery, Burn Center, Hand Center, Sarcoma Reference Center, BG-University Hospital Bergmannsheil, D-44789 Bochum, Germany.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Becerikli
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008080:Liposarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D060787:Neoplasm Grading; D061251:Primary Cell Culture; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013848:Thigh; D059016:Tumor Microenvironment
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin