title: Bone marrow stroma protects myeloma cells from cytotoxic damage via induction of the oncoprotein MUC1.
abstract: Multiple myeloma (MM) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co-culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co-culture of MM cells with stroma cells, on expression of the MUC1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis. Co-culture of stroma with MM cells resulted in increased MUC1 expression by tumour cells. The effect of stromal cell co-culture on MUC1 expression was not dependent on cell contact and was therefore thought to be due to soluble factors secreted by the stromal cells into the microenvironment. We demonstrated that MUC1 expression was mediated by interleukin-6 and subsequent up-regulation of the JAK-STAT pathway. Interestingly, the effect of stromal cell co-culture on tumour resistance was partially reversed by silencing of MUC1 in MM cells, consistent with the potential role of MUC1 in mediating resistance to cytotoxic-based therapies.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Bar-Natan
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Stroopinsky
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Katarina
authors.initials: K
authors.lastname: Luptakova
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Coll
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Arie
authors.initials: A
authors.lastname: Apel
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Athalia R
authors.initials: AR
authors.lastname: Pyzer
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Palmer
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Michaela R
authors.initials: MR
authors.lastname: Reagan
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Myrna R
authors.initials: MR
authors.lastname: Nahas
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Karp Leaf
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Salvia
authors.initials: S
authors.lastname: Jain
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Arnason
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Jacalyn
authors.initials: J
authors.lastname: Rosenblatt
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Avigan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D018396:Mucin-1 / Q000096:biosynthesis* / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D018396:Mucin-1; D061988:Proteasome Inhibitors; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2
keywords: MUC1; STAT-3; bortezomib; multiple myeloma; stroma cells