Subcutaneous passage increases cell aggressiveness in a xenograft model of diffuse large B cell lymphoma

Bosch, Rosa; Moreno, Marı́a José; Dieguez-Gonzalez, Rebeca; Céspedes, María Virtudes; Gallardo, Alberto; Nomdedeu, Josep; Pavón, Miguel Ángel; Espinosa, Íñigo; Mangues, María Antònia; Sierra, Jorge; Casanova, Isolda; Mangues, Ramón

doi:10.1007/s10585-012-9454-8

Cited by 5 publications

(7 citation statements)

References 31 publications

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“…This was in contrast to the direct orthotopic microinjection that generated a non-metastatic model. These results are consistent with our previous report of increased metastases in lymph nodes and bone marrow in a diffuse large B-cell lymphoma model after SC conditioning (Bosch et al, 2012), suggesting that this procedure could be used to increase the metastatic yield of the in-vitro -established cell lines. In both CRC models, SC preconditioning enhanced, in an organ-specific manner, the number of microfoci (colonization) and/or its growth to macrofoci and visible metastases.…”

Section: Discussionsupporting

confidence: 93%

Subcutaneous preconditioning increases invasion and metastatic dissemination in colorectal cancer models

Álamo

Gallardo

Pavón

et al. 2014

Disease Models &Amp; Mechanisms

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Mouse colorectal cancer (CRC) models generated by orthotopic microinjection of human CRC cell lines reproduce the pattern of lymphatic, haematological and transcoelomic spread but generate low metastatic efficiency. Our aim was to develop a new strategy that could increase the metastatic efficiency of these models. We used subcutaneous implantation of the human CRC cell lines HCT116 or SW48 prior to their orthotopic microinjection in the cecum of nude mice (SC+ORT). This subcutaneous preconditioning significantly enhanced metastatic dissemination. In the HCT116 model it increased the number and size of metastatic foci in lymph nodes, lung, liver and peritoneum, whereas, in the SW48 model, it induced a shift from non-metastatic to metastatic. In both models the number of apoptotic bodies in the primary tumour in the SC+ORT group was significantly reduced compared with that in the direct orthotopic injection (ORT) group. Moreover, in HCT116 tumours the number of keratin-positive tumour buddings and single epithelial cells increased at the invasion front in SC+ORT mice. In the SW48 tumour model, we observed a trend towards a higher number of tumour buds and single cells in the SC+ORT group but this did not reach statistical significance. At a molecular level, the enhanced metastatic efficiency observed in the HCT116 SC+ORT model was associated with an increase in AKT activation, VEGF-A overexpression and downregulation of β1 integrin in primary tumour tissue, whereas, in SW48 SC+ORT mice, the level of expression of these proteins remained unchanged. In summary, subcutaneous preconditioning increased the metastatic dissemination of both orthotopic CRC models by increasing tumour cell survival and invasion at the tumour invasion front. This approach could be useful to simultaneously study the mechanisms of metastases and to evaluate anti-metastatic drugs against CRC.

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Section: Discussionsupporting

confidence: 93%

Subcutaneous preconditioning increases invasion and metastatic dissemination in colorectal cancer models

Álamo

Gallardo

Pavón

et al. 2014

Disease Models &Amp; Mechanisms

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“…We next assessed whether U2932 clones would engraft in lymphoid organs of mice upon i.v. delivery; in NSG mice, this was only the case after s.c. passaging, as had been described (14). Interestingly, s.c. passaged CREBBP +/− clones engrafted more readily than their CREBBP +/+ counterparts in recipient bones (Fig.…”

Section: Genome Editing Of Crebbp Mimicking a Patient Mutation Reducementioning

confidence: 74%

Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth

Hashwah

Schmid

Kasser

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

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The genes encoding the histone acetyl-transferases (HATs) CREB binding protein (CREBBP) and EP300 are recurrently mutated in the activated B cell-like and germinal center (GC) B cell-like subtypes of diffuse large B cell lymphoma (DLBCL). Here, we introduced a patient mutation into a human DLBCL cell line using CRISPR and deleted and in the GC B cell compartment of mice. CREBBP-mutant DLBCL clones exhibited reduced histone H3 acetylation, expressed significantly less MHCII, and grew faster than wild-type clones in s.c. and orthotopic xenograft models. Mice lacking Crebbp in GC B cells exhibited hyperproliferation of their GC compartment upon immunization, had reduced MHCII surface expression on GC cells, and developed accelerated MYC-driven lymphomas. Ep300 inactivation reproduced some, but not all, consequences of Crebbp inactivation. MHCII deficiency phenocopied the effects of CREBBP loss in spontaneous and serial transplantation models of MYC-driven lymphomagenesis, supporting the idea that the mutational inactivation of CREBBP promotes immune evasion. Indeed, the depletion of CD4 T cells greatly facilitated the engraftment of lymphoma cells in serial transplantation models. In summary, we provide evidence that both HATs are bona fide tumor suppressors that control MHCII expression and promote tumor immune control; mutational inactivation of CREBBP, but not of EP300, has additional cell-intrinsic engraftment and growth-promoting effects.

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“…In previous studies we developed disseminated lymphoma mouse models by performing subcutaneous conditioning of cells to increase their aggressiveness prior to intravenous injection . Here, we used this approach to evaluate the effect of subcutaneous conditioning of DLBCL cells on CXCR4 expression and its impact on their engraftment and dissemination in vivo .…”

Section: Resultsmentioning

confidence: 99%

CXCR4 expression enhances diffuse large B cell lymphoma dissemination and decreases patient survival

Moreno

Bosch

Dieguez-Gonzalez³

et al. 2014

The Journal of Pathology

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The chemokine receptor CXCR4 has been implicated in the migration and trafficking of malignant B cells in several haematological malignancies. Over‐expression of CXCR4 has been identified in haematological tumours, but data concerning the role of this receptor in diffuse large B cell lymphoma (DLBCL) are lacking. CXCR4 is a marker of poor prognosis in various neoplasms, correlating with metastatic disease and decreased survival of patients. We studied CXCR4 involvement in cell migration in vitro and dissemination in vivo. We also evaluated the prognostic significance of CXCR4 in 94 biopsies of DLBCL patients. We observed that the level of expression of CXCR4 in DLBCL cell lines correlated positively with in vitro migration. Expression of the receptor was also associated with increased engraftment and dissemination, and decreased survival time in NOD/SCID mice. Furthermore, administration of a specific CXCR4 antagonist, AMD3100, decreased dissemination of DLBCL cells in a xenograft mouse model. In addition, we found that CXCR4 expression is an independent prognostic factor for shorter overall survival and progression‐free survival in DLBCL patients. These results show that CXCR4 mediates dissemination of DLBCL cells and define for the first time its value as an independent prognostic marker in DLBCL patients. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

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Subcutaneous passage increases cell aggressiveness in a xenograft model of diffuse large B cell lymphoma

Cited by 5 publications

References 31 publications

Subcutaneous preconditioning increases invasion and metastatic dissemination in colorectal cancer models

Subcutaneous preconditioning increases invasion and metastatic dissemination in colorectal cancer models

Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth

CXCR4 expression enhances diffuse large B cell lymphoma dissemination and decreases patient survival

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