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1.
Matrix Biol ; 120: 60-75, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37201729

RESUMO

Multiple myeloma is a hematological neoplasm derived from plasma cells invariably developing in the bone marrow (BM). The persisting clinical challenge in MM resides in its high ability to resist drugs as shown by the frequent relapses observed in patients regardless of the treatment applied. In a mouse model of MM, we identified a subpopulation of cells harboring increased resistance to current MM drugs. These cells bound a proliferation inducing ligand (APRIL), a key MM promoting/survival factor. APRIL binding involved the heparan sulfate (HS) chain present on syndecan-1 (SDC-1), and correlated with reactivity to the anti-HS antibody 10e4. 10e4+cells had a high proliferation activity, and were able to form colonies in 3-D cultures. 10e4+ cells were the only cells able to develop in BM after intravenous injection. They also resisted drugs in vivo, since their number increased after treatment in BM. Notably, 10e4+ cells differentiated into 10e4- cells upon in vitro and in vivo expansion. Expression of one sulfotransferase, HS3ST3a1, allowed modification of syndecan-1 to confer reactivity to 10e4 and binding to APRIL. HS3ST3a1 deletion inhibited tumorigenesis in BM. Notably, the two populations coexisted at a variable frequency in the BM of MM patients at diagnosis. In total, our results indicate that 3-O-sulfation on SDC-1 carried out by HS3ST3a1 defines aggressive MM cells, and that targeting of this enzyme could possibly be used to better control drug resistance.


Assuntos
Mieloma Múltiplo , Sindecana-1 , Animais , Camundongos , Medula Óssea/metabolismo , Heparitina Sulfato/metabolismo , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Sulfotransferases/genética , Sindecana-1/genética , Sindecana-1/metabolismo
2.
Leukemia ; 31(10): 2114-2121, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28232741

RESUMO

Multiple myeloma (MM) is a plasma cell malignancy where MM cell growth is supported by the bone marrow (BM) microenvironment with poorly defined cellular and molecular mechanisms. MM cells express CD40, a receptor known to activate autocrine secretion of cytokines and elicit proliferation. Activated T helper (Th) cells express CD40 ligand (CD40L) and BM Th cells are significantly increased in MM patients. We hypothesized that activated BM Th cells could support MM cell growth. We here found that activated autologous BM Th cells supported MM cell growth in a contact- and CD40L-dependent manner in vitro. MM cells had retained the ability to activate Th cells that reciprocated and stimulated MM cell proliferation. Autologous BM Th cells supported MM cell growth in xenografted mice and were found in close contact with MM cells. MM cells secreted chemokines that attracted Th cells, secretion was augmented by CD40-stimulation. Within 14 days of culture of whole BM aspirates in autologous serum, MM cells and Th cells mutually stimulated each other, and MM cells required Th cells for further expansion in vitro and in mice. The results suggest that Th cells may support the expansion of MM cells in patients.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Mieloma Múltiplo/patologia , Linfócitos T Auxiliares-Indutores/transplante , Evasão Tumoral/imunologia , Idoso , Animais , Apresentação de Antígeno , Antígenos CD40/imunologia , Ligante de CD40/imunologia , Divisão Celular , Quimiocinas/metabolismo , Quimiotaxia de Leucócito , Técnicas de Cocultura , Citocinas/metabolismo , Sobrevivência de Enxerto/imunologia , Xenoenxertos , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/terapia , Linfócitos T Auxiliares-Indutores/imunologia , Transplante Autólogo/efeitos adversos , Microambiente Tumoral
4.
Lupus ; 18(4): 355-60, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19276304

RESUMO

Lupus nephritis is associated with thickening of the glomerular extracellular membranes. Distribution of collagen IV alpha-chains in the glomerular basement membrane in kidneys of lupus-prone B/W mice has been examined in this study. The results are indicative of a qualitative change in the collagen IV matrix occurring around the time of development of proteinuria, with an embryonic alpha1/alpha2 isoform replacing the normal glomerular basement membrane (GBM). These changes mimic alterations seen in Alport syndrome and coincide with an increase in collagenolytic activity within the glomerulus. It has been hypothesized that alterations in collagen matrix synthesis represent compensatory responses to an increase in GBM proteolysis and could represent an important step in the pathogenesis of nephritis through the formation of a dysfunctional glomerular filter. Also, aberrations in the collagen matrix composition could contribute to the deposition of autoantibodies within the glomerulus.


Assuntos
Colágeno Tipo IV/metabolismo , Membrana Basal Glomerular/metabolismo , Nefrite Lúpica/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Membrana Basal Glomerular/fisiopatologia , Glomérulos Renais/metabolismo , Glomérulos Renais/fisiopatologia , Nefrite Lúpica/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NZB , Isoformas de Proteínas , Proteinúria/etiologia
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