Macrophages in Waldenstrom Macroglobulinemia: Implications for the Tumor Microenvironment
Notice bibliographique
Résumé
Waldenstrom Macroglobulinemia (WM) is a non-Hodgkin B-cell lymphoma, characterized by infiltration of the bone marrow with plasma cells and lymphocytes. The microenvironment surrounding malignant cells (tumor microenvironment; TME) has been shown to play an important role in the progression of WM, however, the effects of macrophages on WM biology have yet to be elucidated. Here, we show that macrophages are present in the WM TME, and that the direct co-culture of M0 and M2, but not M1 macrophages, derived from THP-1 human cell line, healthy human donor peripheral blood, or murine bone-marrow derived macrophages, with WM cell lines, promotes WM cell growth and survival, in vitro. First, to assess whether macrophages could be involved in WM progression, confirmed cases of lymphoplasmacytic lymphoma (LPL)/WM were identified by pathology and clinical record (Kingston General Hospital, Kingston, ON, Canada). Several bone marrow and lymph node (when available) sections were retrieved and stained for human macrophage antigens CD14 and CD68. We show that macrophages are present in the WM microenvironment, and are found in close proximity to malignant cells. We also show that some macrophages were present and associated with WM cells in tumor samples from SCID mice that were injected with WM cell lines (BCWM.1 and RPCI-WM1) and bone marrow stromal cells (HS-5) stained with H&E staining. To assess the effect of these WM-associated macrophages, macrophages were first derived from THP-1 human cell line monocytes, healthy human peripheral blood donor, or C57BL6J bone marrow aspirate. Macrophages were treated with the appropriate cytokine cocktail to induce M1 or M2 polarization states. M0 and M2 macrophages derived from all three sources, directly co-cultured with WM cells (1:1) for 72 hours, increased the proliferation and survival of WM cells, compared to WM cells grown alone. Additionally, M1 macrophages did not induce a proliferative effect, and in some cases, decreased the proliferation and viability of WM cells. M2 macrophages have been shown to have a pro-proliferative effect in several other cancers, but M0 macrophages were not expected to have this effect. To address why M0 macrophages were also inducing this pro-proliferative and pro-survival effect, WM cells were co-cultured for 72 hours with M0 macrophages generated from cell line, human donor, or murine bone marrow. Co-culture of WM cells with M0 macrophages induced the expression of M2-associated genes in these macrophages, indicating that WM cells are preferentially inducing macrophages towards an M2 phenotype to further aid themselves in progression. Our group has previously investigated the role of GLI transcription factors in myeloid cell biology and found that activation of macrophages with LPS induces GLI3 expression. To investigate mechanisms underlying the pro-tumorigenic macrophage-malignant cell relationship, we performed an analysis of RNA-sequencing data using macrophages from mice lacking Gli3 in myeloid cells (M-Gli3-/- mice) stimulated with LPS. Through this, a subset of genes that are differentially expressed in the absence of GLI3 were identified and it suggested that GLI3 may play role in promoting M2 macrophage polarization. Confirming our results, we found that GLI3 expression is induced in M2 but not M1 macrophages and this is supported by public RNA-sequencing data showing an induction in Gli3 expression in murine M2 macrophages. We found that macrophages from M-Gli3-/- mice did not induce WM cell proliferation and there was a significant reduction in the survival of WM cells cocultured with M2 macrophages from M-Gli3-/- mice compared to WT mice. In addition, M-Gli3-/- M0 macrophages cultured in M2 polarizing media did not express Cd163, an M2 marker, despite the induction of iNos expression (M1 marker) when M0 cells were cultured in M1 polarizing conditions. Finally, macrophages lacking Gli3 were unable to increase the proliferation and survival of WM cells, implicating a role for GLI3 in macrophage polarization and subsequent effects on WM cell growth and proliferation. Taken together, these results suggest a role for M2 macrophages in promoting WM cell growth and survival and identify GLI3 as a modulator of macrophage polarization in the WM tumor microenvironment.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».