Tonsil-Derived Mesenchymal Stem Cells Inhibit the Proliferation of Hematological Cancer Cells through Downregulation of IL-6 Gene Expression under Hyperthermia

Mapping Intimacies ◽

10.21203/rs.3.rs-1137806/v1 ◽

2021 ◽

Author(s):

Melek Yüce ◽

Esra Albayrak

Keyword(s):

Stem Cells ◽

Cancer Treatment ◽

Cancer Cells ◽

K562 Cells ◽

Lymphoid Organs ◽

Cellular Interaction ◽

Viable Cell Number ◽

Transcriptional Level ◽

Hematological Cancer ◽

Secondary Lymphoid Organs

Abstract Stem cells are extensively being studied as promising biological therapeutic candidates in cancer treatment. In various cancer types, some studies show proliferative effects while others show inhibitory effects of MSCs on tumors. Some studies have reported that MSCs isolated from different sources display different anti-cancer properties. Tonsils are one of the secondary lymphoid organs that form an important part of the immune system and located at the mucosal interface. The relation between secondary lymphoid organs and cancer progression lead us to investigate the effect of tonsil-derived MSCs (T-MSC) on cancer treatment. Therefore, we aimed to determine the anti-tumoral effects of tonsil-derived MSCs cultured at febrile temperature on hematological cancer cell lines. We found that co-culture of K562 cells and MOLT-4 with T-MSCs significantly decreased the viable cell number post 7 days of the culture under the febrile and normal culture conditions. Besides, the T-MSC co-culture not only induced the apoptosis on K562 and MOLT-4 cells but also, induced the cell cycle arrest at G2-M phase on MOLT-4 cells. The apoptotic effect of T-MSC co-culture under febrile stimulation was confirmed by upregulation of Bax, c-myc genes for K562 cells and upregulation of Bax, p53 and c-myc genes for MOLT-4 cells in transcriptional level. Our study has contributed to highlight the effect of the cellular interaction between the T-MSCs and human hematological cancer cells during in vitro co-culture under hyperthermia for tumor progression. In the light of these results, we indicated that tonsil-derived MSCs have promising therapeutic potential for cancer therapy.

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Human Mesenchymal Stem Cells Isolated from Bone Marrow and Lymphoid Organs Support Tumor B-Cell Growth: Implications in Follicular Lymphoma Pathogenesis.

Blood ◽

10.1182/blood.v108.11.2409.2409 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2409-2409

Author(s):

Karin Tarte ◽

Patricia Ame-Thomas ◽

Hélène Maby-El Hajjami ◽

Céline Monvoisin ◽

Rachel Jean ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cell Migration ◽

Cell Growth ◽

B Cell ◽

Stromal Cells ◽

Lymphoid Organs ◽

Reticular Cells ◽

Secondary Lymphoid Organs

Abstract There is accumulating evidence that cellular microenvironment plays a key role in follicular lymphoma (FL) pathogenesis, both within tumor lymph nodes (LN) and in infiltrated bone marrow (BM) where ectopic LN-like reticular cells are integrated within malignant B-cell nodular aggregates. In normal secondary lymphoid organs, specific stromal cell subsets provide a highly specialized microenvironment that supports immune response. In particular, fibroblastic reticular cells (FRC) mediate immune cell migration, adhesion, and reciprocal interactions. The role of FRC and their postulated progenitors, i.e. bone marrow mesenchymal stem cells (MSC), in FL remains unexplored. In this study, we have investigated the relationships between FRC and MSC and their capacity to sustain malignant B-cell growth. Our findings strongly suggest that secondary lymphoid organs contain bona-fide MSC able to give rise at single-cell level to adipocytes, chondrocytes, and osteoblasts. These LN-derived MSC could also differentiate, in response to a combination of tumor necrosis factor-α (TNF) and lymphotoxin-α1β2 (LT), into fully functional FRC, able to construct a dense extracellular reticular meshwork positive for transglutaminase and fibronectin staining, to produce inflammatory (CXCL9, CXCL10, CCL5, CCL2) and LN-specific (CCL19) chemokines, and to favour lymphoma B-cell growth. Bone marrow-derived MSC (BM-MSC) acquire in vitro a complete FRC phenotype in the same culture conditions. As an exemple, BM-MSC had a strong, although not complete, protective effect on serum deprivation-induced apoptosis of BL2 cell line (mean percentage of CD20posCaspase-3pos cells: 24.8 +/− 17.5% in coculture with BM-MSC versus 80.7 +/- 10.4% in medium alone; P < .05; n =5) and pretreatment with TNF/LT fully restored BL2 viability (mean percentage of CD20posCaspase-3pos cells: 7.4 +/− 4.7%; P < .05; n = 5). Moreover, stimulation of stromal cells by TNF/LT before coculture enhanced the number of viable CD19pos primary FL B cells by 2.4-fold for BM-MSC and 2.3 fold for LN-MSC compared with the culture without stromal cells (P < .05; n = 6). Interestingly, cell contact with lymphoma B-cell lines or purified FL B cells trigger the differentiation of BM-MSC into FRC that, in turn, support malignant B-cell migration, adhesion and survival. Altogether, these new insights into the interactions between lymphoma cells and their microenvironment could offer original therapeutic strategies.

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Upregulation of CC Chemokine Receptor 7 (CCR7) Enables Migration of Xenogeneic Human Adipose-Derived Mesenchymal Stem Cells to Rat Secondary Lymphoid Organs

Medical Science Monitor ◽

10.12659/msm.902690 ◽

2016 ◽

Vol 22 ◽

pp. 5206-5217 ◽

Cited By ~ 5

Author(s):

Tian Ma ◽

Shao-Liang Luan ◽

Hong Huang ◽

Xing-Kun Sun ◽

Yan-Mei Yang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Chemokine Receptor ◽

Lymphoid Organs ◽

Cc Chemokine ◽

Secondary Lymphoid Organs ◽

Cc Chemokine Receptor 7

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Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis

Blood ◽

10.1182/blood-2006-05-020800 ◽

2006 ◽

Vol 109 (2) ◽

pp. 693-702 ◽

Cited By ~ 143

Author(s):

Patricia Amé-Thomas ◽

Hélène Maby-El Hajjami ◽

Céline Monvoisin ◽

Rachel Jean ◽

Delphine Monnier ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cell Growth ◽

Follicular Lymphoma ◽

B Cell ◽

Lymphoid Organs ◽

Reticular Cells ◽

Secondary Lymphoid Organs

Abstract Accumulating evidence indicates that the cellular microenvironment plays a key role in follicular lymphoma (FL) pathogenesis, both within tumor lymph nodes (LNs) and in infiltrated bone marrow where ectopic LN-like reticular cells are integrated within malignant B-cell nodular aggregates. In normal secondary lymphoid organs, specific stromal cell subsets provide a highly specialized microenvironment that supports immune response. In particular, fibroblastic reticular cells (FRCs) mediate immune cell migration, adhesion, and reciprocal interactions. The role of FRCs and their postulated progenitors, that is, bone marrow mesenchymal stem cells (MSCs), in FL remains unexplored. In this study, we investigated the relationships between FRCs and MSCs and their capacity to sustain malignant B-cell growth. Our findings strongly suggest that secondary lymphoid organs contain MSCs able to give rise to adipocytes, chondrocytes, osteoblasts, as well as fully functional B-cell supportive FRCs. In vitro, bone marrow–derived MSCs acquire a complete FRC phenotype in response to a combination of tumor necrosis factor-α and lymphotoxin-α1β2. Moreover, MSCs recruit primary FL cells that, in turn, trigger their differentiation into FRCs, making them able to support malignant B-cell survival. Altogether, these new insights into the cross talk between lymphoma cells and their microenvironment could offer original therapeutic strategies.

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9-(2-Phosphonyl-methoxyethyl)-adenine promotes erythrocytic differentiation and disrupts cell replication in chronic myelogenous leukemia K562 cells

MacEwan University Student eJournal ◽

10.31542/muse.v5i1.2000 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Brittany Wiseman

Keyword(s):

Cancer Treatment ◽

Cancer Cells ◽

Chronic Myelogenous Leukemia ◽

Cellular Differentiation ◽

K562 Cells ◽

Myelogenous Leukemia ◽

Cell Replication ◽

Protein Subunit ◽

Hematopoietic Stem ◽

Gamma Globin

Disruption during cellular differentiation can cause hematopoietic stem cells to proliferate uncontrollably, resulting in the development of cancer. Differentiation therapies are being investigated as a type of cancer treatment which involve inducing agents that promote the differentiation of cancer cells into those with similar properties to normal blood cells. These cells can then undergo apoptosis at an accelerated and controlled rate compared to cancer cells, making this a potential therapeutic technique. In this study, the ability of human chronic myelogenous leukemia K562 cells to undergo cellular differentiation in response to the inducing agent 9-(2-Phosphonyl-methoxy ethyl)-adenine (PMEA) is investigated. PMEA has previously been shown to disrupt cell replication, and promote erythrocytic differentiation in K562 cells. In order to further test the effectiveness of this inducer, cell proliferation was measured with a cell growth curve, hemoglobin presence was measured with benzidine staining, and gamma-globin expression (a protein subunit of fetal hemoglobin) was measured in both induced and uninduced K562 cell cultures via RT-qPCR and western blotting. The results indicate that PMEA slows cell replication, and promotes hemoglobin (and subsequently gamma-globin) expression in treated cells. In summary, the findings support the conclusion that PMEA is able to promote erythrocytic differentiation in K562 cells, and provides information that supports differentiation therapies as a method for cancer treatment.

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Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment

Stem Cells International ◽

10.1155/2018/5416923 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 124

Author(s):

Lan Thi Hanh Phi ◽

Ita Novita Sari ◽

Ying-Gui Yang ◽

Sang-Hyun Lee ◽

Nayoung Jun ◽

...

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Cancer Treatment ◽

Cancer Cells ◽

Therapeutic Agents ◽

Therapeutic Approaches ◽

Tumor Initiating Cells ◽

Therapeutic Implications ◽

Key Features

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are suggested to be responsible for drug resistance and cancer relapse due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Thus, it is important to understand the characteristics and mechanisms by which CSCs display resistance to therapeutic agents. In this review, we highlight the key features and mechanisms that regulate CSC function in drug resistance as well as recent breakthroughs of therapeutic approaches for targeting CSCs. This promises new insights of CSCs in drug resistance and provides better therapeutic rationales to accompany novel anticancer therapeutics.

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Dynamism, Sensitivity, and Consequences of Mesenchymal and Stem-Like Phenotype of Cancer Cells

Stem Cells International ◽

10.1155/2018/4516454 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Petra Gener ◽

Joaquin Seras-Franzoso ◽

Patricia González Callejo ◽

Fernanda Andrade ◽

Diana Rafael ◽

...

Keyword(s):

Stem Cells ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Cancer Treatment ◽

Cancer Cells ◽

Cell Types ◽

Mesenchymal Phenotype ◽

Metastatic Growth ◽

Anticancer Treatment

There are remarkable similarities in the description of cancer stem cells (CSCs) and cancer cells with mesenchymal phenotype. Both cell types are highly tumorigenic, resistant against common anticancer treatment, and thought to cause metastatic growth. Moreover, cancer cells are able to switch between CSC and non-CSC phenotypes and vice versa, to ensure the necessary balance within the tumor. Likewise, cancer cells can switch between epithelial and mesenchymal phenotypes via well-described transition (EMT/MET) that is thought to be crucial for tumor propagation. In this review, we discuss whether, and to which extend, the CSCs and mesenchymal cancer cells are overlapping phenomena in terms of mechanisms, origin, and implication for cancer treatment. As well, we describe the dynamism of both phenotypes and involvement of the tumor microenvironment in CSC reversion and in EMT.

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Human Mesenchymal Stem Cells as Precursors of Functional Fibroblastic Reticular Cells: Implications for the Physiopathology of Secondary Lymphoid Organs.

Blood ◽

10.1182/blood.v106.11.2310.2310 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2310-2310

Author(s):

Karin Tarte ◽

Patricia Ame-Thomas ◽

Hélène Maby ◽

Sylvie Caulet-Maugendre ◽

Rachel Jean ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Lymph Node ◽

Stromal Cells ◽

Stromal Cell ◽

Lymphoid Organs ◽

Tnf Α ◽

Reticular Cells ◽

Secondary Lymphoid Organs

Abstract Several subsets of stromal cells are found among secondary lymphoid organs where they play a key role in the initiation and maintenance of immune response. In particular, fibroblastic reticular cells (FRC) of the paracortex secrete extracellular matrix (ECM) components that constitute a dense network of conduits allowing antigens carried within the subcapsular afferent lymph to reach the lumen of the medullary high endothelial venules. FRC produce also several chemokines that recruit T, B, and dendritic cells from blood and favour their reciprocal interactions. In addition, follicular dendritic cells (FDC) are located exclusively into germinal centers and allow normal B-cell selection through a complex set of survival signals, including BCR-mediated signal, chemokines and adhesion molecules. FRC and FDC networks are phenotypically and probably functionally altered during development of follicular lymphomas and diffuse large B cell lymphomas, the two most frequent Non-Hodgkin Lymphomas. FRC and FDC are supposed to be of mesenchymal origin even if no conclusive work has been conducted to date in human. We have obtained 15 tonsil-derived stromal cell lines, that displayed all the morphologic, phenotypic, and functional characteristics of FRC, including synthesis of inflammatory (CXCL10, CXCL9, CCL5) and lymph-node specific (CCL19, CCL21) chemokines, and secretion of ECM organized in a reticular meshwork after long-term culture in the presence of TNF-α and lymphotoxin-α1β2 (LT). These cells induced tonsil leukocyte migration and adhesion in vitro. Tonsil-derived stromal cells expressed LTβR, TNFR, and CD40 but were negative for FDC specific markers, such as CD21 or CXCL13, even following in vitro stimulation by TNF-α, LT, and trimeric CD40L. Interestingly, such TNF and LT-dependent FRC differentiation could also be induced in adult bone marrow-derived mesenchymal stem cells (MSC). In addition, MSC-like cells able to differentiate along osteogenic, adipogenic, and chondrogenic lineages at the clonal level were found in normal tonsils. These data shed new lights on our current understanding of lymph node stromal cell origin and strongly suggest that MSC are the precursors of FRC in secondary lymphoid organs, and perhaps in bone marrow in case of FL involvement where ectopic lymph node-like stromal cells are detected in close association with tumor cells. In conclusion, MSC and their progeny trigger differential immune effects, depending on cytokine context, localization and cell contact with immune cells. These properties are probably modified during lymphomas where the contact between malignant B cells and stromal cells is crucial for tumor development.

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