title: Merkel cell carcinoma expresses vasculogenic mimicry: demonstration in patients and experimental manipulation in xenografts.
abstract: Merkel cell carcinoma (MCC) is a highly virulent cutaneous neoplasm that, like melanoma, is a frequent cause of patient morbidity and mortality. The cellular mechanisms responsible for the aggressive behavior of MCC remain unknown. Vasculogenic mimicry (VM) is a phenomenon associated with cancer virulence, including in melanoma, whereby anastomosing laminin networks form in association with tumor cells that express certain endothelial genes. To determine whether VM is a factor in MCC, we employed a relevant xenograft model using two independent human MCC lines. Experimentally induced tumors were remarkably similar histologically to patient MCC, and both contained laminin networks associated with vascular endothelial-cadherin (CD144) and vascular endothelial growth factor receptor 1, as well as Nodal expression typical of VM in melanoma. Moreover, two established chemotherapeutic agents utilized for human MCC, etoposide and carboplatin, induced necrosis in xenografts on systemic administration while enriching for laminin networks in apparently resistant viable tumor regions that persisted. These findings for the first time establish VM-like laminin networks as a biomarker in MCC, demonstrate the experimental utility of the MCC xenograft model, and suggest that VM-rich regions of MCC may be refractory to conventional chemotherapeutic agents.
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lezcano
authors.affiliation: 1] Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kleffel
authors.affiliation: 1] Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Lee
authors.affiliation: 1] Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Larson
authors.affiliation: 1] Harvard Medical School, Boston, MA, USA [2] Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: 1] Harvard Medical School, Boston, MA, USA [2] Center for Cutaneous Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: DoRosario
authors.affiliation: Institute for Cancer Care, Mercy Medical Center, Baltimore, MD, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Wang
authors.affiliation: 1] Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA [3] Transplantation Research Center, Children's Hospital, Boston, MA, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
authors.affiliation: 1] Harvard Medical School, Boston, MA, USA [2] Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D016190:Carboplatin / Q000627:therapeutic use; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D005047:Etoposide / Q000627:therapeutic use; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D018345:Mice, Knockout; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011897:Random Allocation; D012867:Skin / Q000473:pathology*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014183:Transplantation, Heterologous
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D016190:Carboplatin
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