Hetero-cellular interaction between cancer cells and stem cells in cancer metastasis

Abstract Mitochondrial dysfunction has been linked to many diseases including organ degeneration and cancer. Mesenchymal stem cells/stromal cells (MSCs) provide a valuable source for stem cell-based therapy and represent an emerging therapeutic approach for tissue regeneration. Increasing evidence suggests that MSCs can directly donate mitochondria to recover from cell injury and rescue mitochondrial damage-provoked tissue degeneration. Meanwhile, cancer cells and cancer stromal cells also cross-talk through mitochondrial exchange to regulate cancer metastasis. This review summarizes the research on MSCs and their mitochondrial transfer. It provides an overview of the biology, function, niches and signaling that play a role in tissue repair. It also highlights the pathologies of cancer growth and metastasis linked to mitochondrial exchange between cancer cells and surrounding stromal cells. It becomes evident that the function of MSC mitochondrial transfer is a double-edged sword. MSC mitochondrial transfer may be a pharmaceutical target for tissue repair and cancer therapy.

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Cancer-educated mesenchymal stem cells promote the survival of cancer cells at primary and distant metastatic sites via the expansion of bone marrow-derived-PMN-MDSCs

Cell Death and Disease ◽

10.1038/s41419-019-2149-1 ◽

2019 ◽

Vol 10 (12) ◽

Cited By ~ 2

Author(s):

Buqing Sai ◽

Yafei Dai ◽

Songqing Fan ◽

Fan Wang ◽

Lujuan Wang ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cancer Cells ◽

Cancer Metastasis ◽

Primary Tumour ◽

Lung Cancer Cells ◽

Gm Csf ◽

Metastatic Sites

AbstractBone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that can differentiate into a variety of cell types. BMSCs are chemotactically guided towards the cancer cells and contribute to the formation of a cancer microenvironment. The homing of BMSCs was affected by various factors. Disseminated tumour cells (DTCs) in distant organs, especially in the bone marrow, are the source of cancer metastasis and cancer relapse. DTC survival is also determined by the microenvironment. Here we aim to elucidate how cancer-educated BMSCs promote the survival of cancer cells at primary tumour sites and distant sites. We highlight the dynamic change by identifying different gene expression signatures in intratumoral BMSCs and in BMSCs that move back in the bone marrow. Intratumoral BMSCs acquire high mobility and displayed immunosuppressive effects. Intratumoral BMSCs that ultimately home to the bone marrow exhibit a strong immunosuppressive function. Cancer-educated BMSCs promote the survival of lung cancer cells via expansion of MDSCs in bone marrow, primary tumour sites and metastatic sites. These Ly6G+ MDSCs suppress proliferation of T cells. CXCL5, nitric oxide and GM-CSF produced by cancer-educated BMSCs contribute to the formation of malignant microenvironments. Treatment with CXCL5 antibody, the iNOS inhibitor 1400w and GM-CSF antibody reduced MDSC expansion in the bone marrow, primary tumour sites and metastatic sites, and promoted the efficiency of PD-L1 antibody. Our study reveals that cancer-educated BMSCs are the component of the niche for primary lung cancer cells and DTCs, and that they can be the target for immunotherapy.

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Engineering liver microtissues to study the fusion of HepG2 with mesenchymal stem cells and invasive potential of fused cells

Biofabrication ◽

10.1088/1758-5090/ac36de ◽

2021 ◽

Author(s):

Junmin Lee ◽

Aly Ung ◽

Hanjun Kim ◽

KangJu Lee ◽

Hyun-Jong Cho ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Human Mesenchymal Stem Cells ◽

Hybrid Cells ◽

Invasive Potential ◽

Mesenchymal Transition ◽

Matrix Deposition

Abstract Increasing evidence from cancer cell fusion with different cell types in the tumor microenvironment has suggested a probable mechanism for how metastasis-initiating cells could be generated in tumors. Although human mesenchymal stem cells (hMSCs) have been known as promising candidates to create hybrid cells with cancer cells, the role of hMSCs in fusion with cancer cells is still controversial. Here, we fabricated a liver-on-a-chip platform to monitor the fusion of liver hepatocellular cells (HepG2) with hMSCs and study their invasive potential. We demonstrated that hMSCs might play dual roles in HepG2 spheroids. The analysis of tumor growth with different fractions of hMSCs in HepG2 spheroids revealed hMSCs’ role in preventing HepG2 growth and proliferation, while the hMSCs presented in the HepG2 spheroids led to the generation of HepG2-hMSC hybrid cells with much higher invasiveness compared to HepG2. These invasive HepG2-hMSC hybrid cells expressed high levels of markers associated with stemness, proliferation, epithelial to mesenchymal transition, and matrix deposition, which corresponded to the expression of these markers for hMSCs escaping from hMSC spheroids. In addition, these fused cells were responsible for collective invasion following HepG2 by depositing Collagen I and Fibronectin in their surrounding microenvironment. Furthermore, we showed that hepatic stellate cells (HSCs) could also be fused with HepG2, and the HepG2-HSC hybrid cells possessed similar features to those from HepG2-hMSC fusion. This fusion of HepG2 with liver-resident HSCs may propose a new potential mechanism of hepatic cancer metastasis.

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Ovarian Cancer Stemness: Biological and Clinical Implications for Metastasis and Chemotherapy Resistance

Cancers ◽

10.3390/cancers11070907 ◽

2019 ◽

Vol 11 (7) ◽

pp. 907 ◽

Cited By ~ 9

Author(s):

Takeshi Motohara ◽

Hidetaka Katabuchi

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Cancer Cells ◽

Cancer Metastasis ◽

Chemotherapy Resistance ◽

Clinical Implications ◽

Ovarian Cancer Stem Cells

Epithelial ovarian cancer is a highly lethal gynecological malignancy that is characterized by the early development of disseminated metastasis. Though ovarian cancer has been generally considered to preferentially metastasize via direct transcoelomic dissemination instead of the hematogenous route, emerging evidence has indicated that the hematogenous spread of cancer cells plays a larger role in ovarian cancer metastasis than previously thought. Considering the distinctive biology of ovarian cancer, an in-depth understanding of the biological and molecular mechanisms that drive metastasis is critical for developing effective therapeutic strategies against this fatal disease. The recent “cancer stem cell theory” postulates that cancer stem cells are principally responsible for tumor initiation, metastasis, and chemotherapy resistance. Even though the hallmarks of ovarian cancer stem cells have not yet been completely elucidated, metastasized ovarian cancer cells, which have a high degree of chemoresistance, seem to manifest cancer stem cell properties and play a key role during relapse at metastatic sites. Herein, we review our current understanding of the cell-biological mechanisms that regulate ovarian cancer metastasis and chemotherapy resistance, with a pivotal focus on ovarian cancer stem cells, and discuss the potential clinical implications of evolving cancer stem cell research and resultant novel therapeutic approaches.

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The regulatory effect of hyaluronan on human mesenchymal stem cells’ fate modulates their interaction with cancer cells in vitro

Scientific Reports ◽

10.1038/s41598-021-00754-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Christian Vogeley ◽

Özer Degistirici ◽

Sören Twarock ◽

Jessica Wladarz ◽

Oliver Reiners ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cancer Cells ◽

Cancer Metastasis ◽

Adipogenic Differentiation ◽

Central Component ◽

Metastatic Niche ◽

Mesenchymal Transition ◽

The Impact

AbstractMetastatic spread of cancer cells into a pre-metastatic niche is highly dependent on a supporting microenvironment. Human bone marrow-derived mesenchymal stem cells (bmMSCs) contribute to the tumor microenvironment and promote cancer metastasis by inducing epithelial-to-mesenchymal transition and immune evasion. The underlying mechanisms, however, are incompletely understood. The glycosaminoglycan hyaluronan (HA) is a central component of the extracellular matrix and has been shown to harbor pro-metastatic properties. In this study we investigated the highly disseminating breast cancer and glioblastoma multiforme cell lines MDA-MB-321 and U87-MG which strongly differ in their metastatic potential to evaluate the impact of HA on tumor promoting features of bmMSC and their interaction with tumor cells. We show that adipogenic differentiation of bmMSC is regulated by the HA-matrix. This study reveals that MDA-MB-231 cells inhibit this process by the induction of HA-synthesis in bmMSCs and thus preserve the pro-tumorigenic properties of bmMSC. Furthermore, we show that adhesion of MDA-MB-231 cells to bmMSC is facilitated by the tumor cell-induced HA-rich matrix and is mediated by the HA-receptor LAYN. We postulate that invasive breast cancer cells modulate the HA-matrix of bmMSC to adapt the pre-metastatic niche. Thus, the HA-matrix provides a potential novel therapeutic target to prevent cancer metastasis.

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

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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Targeting Cancer Stem Cells with Repurposed Drugs to Improve Current Therapies

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892816666210208232251 ◽

2021 ◽

Vol 16 ◽

Author(s):

Dunne Fong ◽

Chase T. Christensen ◽

Marion M. Chan

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Cancer Care ◽

Cancer Metastasis ◽

Psychotic Disorders ◽

Inflammatory Diseases ◽

Fatal Outcome ◽

Cell Types ◽

Repurposed Drugs

Background: Cancer is a multistep process involving genetic and epigenetic changes in the somatic genome. Genetic mutations as well as environmental factors lead to the initiation, promotion, and progression of cancer. Metastasis allows cancer cells to spread via circulatory and lymphatic systems; secondary tumorigenesis typically leads to a fatal outcome. Recent experimental evidence suggests Cancer Stem Cells (CSCs) play a pivotal role in tumor progression. A tumor is heterogeneous and composed of different cell types. CSCs are a subpopulation of tumor cells possessing abilities to self-renew and differentiate. Objective: To present repurposed drugs, and potential candidates, that can serve as anticancer medications intended to target resistant cancer cells, i.e. CSCs. Methods: Research publications, FDA filings, and patents have been reviewed for repurposed drugs or drug combinations that can act to improve cancer care. Results: Drugs that act against CSCs include ones approved for treatment of diabetes (metformin & thiazolidinediones), parasitic diseases (chloroquine, niclosamide, mebendazole & pyrvinium), psychotic disorders (thioridazine, clomipramine & phenothiazines), alcoholism (disulfiram), lipid disorder (statins), inflammatory diseases (tranilast, auranofin, acetaminophen & celecoxib), antibiotics (azithromycin), and other disorders. Current research findings advocate the existence of beneficial effects by combining these repurposed drugs, and also through their complementary use with conventional cancer therapies. Conclusion: Repurposing FDA-approved medications towards cancer care, by targeting the resistant CSCs, will allow for a quicker, cheaper development and approval process. A larger drug library available to physicians will allow for increased efficacy during both first-line and recurrent cancer treatments.

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