The Impact of HIFU Ablation on the Histopathological Features of Locally Recurrent Fibroids Tissue Post-HIFU Treatment.

OBJECTIVE: To evaluate the impact of high-intensity focused ultrasound (HIFU) ablation on the histopathological features of locally recurrent fibroids tissue. METHODS: Patients who underwent transabdominal hysterectomy or myomectomy for uterine fibroids from January 1, 2021 to July 1, 2023 at a teaching hospital in China were enrolled in this prospective study. The patients who underwent surgery for local recurrence of uterine fibroids after HIFU ablation were categorized as the HIFU group, and patients who had not undergone HIFU ablation for uterine fibroids were the control group. Hematoxylin-eosin (HE) staining, Masson staining, and immunohistochemical staining were performed to analyze the counts of smooth muscle cells (SMCs), collagen content, microvascular count, and the expression levels of estrogen receptor (ER) and progesterone receptor (PR) in the fibroid tissue specimens. RESULTS: The mean SMC counts in the HIFU and control groups were 337.68/field and 328.52/field respectively. The mean collagen content in the HIFU group and control group were 46.06% and 41.69% respectively. The mean microvessel counts in the HIFU group and control group were 13.66/field and 14.08/field respectively. The mean ER scores in the HIFU and control groups were 6.9 and 7.47 respectively, and the mean PR scores were 7.3 and 7.56 respectively. Overall, there were no significant differences in the SMC counts, collagen content, microvascular counts, and the ER and PR expression levels between the HIFU group and control group (p > 0.05). CONCLUSIONS: HIFU ablation has no effect on the pathological characteristics of local recurrent fibroid tissue, and is an ideal non-invasive treatment option.

Novel lncRNA Gm33149 modulates metastatic heterogeneity in melanoma by regulating the miR-5623-3p/Wnt axis via exosomal transfer.

The high mortality rate associated with melanoma primarily results from metastasis and recurrence. However, the precise mechanisms driving these processes remain poorly understood. Intercellular communication between cancer cells and non-cancer cells significantly influences the tumor microenvironment and plays a crucial role in metastasis. Therefore, our current study aims to investigate the role and mechanism of long non-coding RNAs (lncRNAs) in regulating the interaction between melanoma cancer stem cells (CSCs) and non-CSCs during the metastatic colonization process. This study has characterized a novel lncRNA called Gm33149. Importantly, we provide evidence for the first time that Gm33149, originating from highly metastatic melanoma stem cells (OL-SD), can be packaged into exosomes and transferred to low-metastatic nonstem cells (OL). Once internalized by OL cells, Gm33149 exerts its function through a competitive endogenous RNA mechanism (ceRNA) involving miR-5623-3p. Specifically, Gm33149 competitively binds to miR-5623-3p, thereby activating the Wnt signaling pathway and promoting the acquisition of a more aggressive metastatic phenotype by OL cells. In summary, our findings suggest that targeting lncRNA Gm33149 within extracellular vesicles could potentially serve as a therapeutic strategy for the treatment of metastatic melanoma. Schematic representation of the mechanisms underlying the pro-metastatic activity of lncRNA Gm33149 mediated by exosomal transfer. The figure illustrates the key mechanisms involved in the pro-metastatic activity of lncRNA Gm33149 through exosomal transfer. Melanoma stem cells (OLSD) release exosomes containing lncRNA Gm33149. These exosomes are taken up by non-stem melanoma cells (OL), delivering lncRNA Gm33149 to the recipient cells. Within OL cells, lncRNA Gm33149 functions as a competitive endogenous RNA (ceRNA), sequestering miR-5623-3p. This sequestration prevents miR-5623-3p from binding to its target genes, thereby activating the Wnt signaling pathway. The activated Wnt signaling pathway enhances the migration, invasion, and metastatic colonization capabilities of OL cells. The transfer of lncRNA Gm33149 via exosomes contributes to OL cells acquiring "metastatic competency" while promoting their metastatic colonization. These findings underscore the importance of lncRNA Gm33149 in intercellular communication and the metastatic progression of melanoma.

A novel lung cancer stem cell extracellular vesicles lncRNA ROLLCSC modulate non-stemness cancer cell plasticity through miR-5623-3p and miR-217-5p targeting lipid metabolism.

BACKGROUND: The high mortality rate of lung cancer is largely attributed to metastasis. Lung cancer stem cells (CSC) are conducive to cancer heterogeneity. Long noncoding RNAs are known to participate in various biological processes regulating the development of lung cancer. However, characterization of the role and mechanisms of lncRNA in lung cancer metastasis remains a challenge. RESULTS: We demonstrate that ROLLCSC, a highly expressed lncRNA in LLC-SDs, promotes the metastasis of the low metastatic LLCs both in vitro and in vivo. ROLLCSC can be transferred from LLC-SD to LLC through encapsulation in extracellular vesicles (EVs), ultimately leading to the enhancement of the metastatic phenotype of LLCs. Mechanistically, we demonstrate that the pro-metastatic activity of ROLLCSC is achieved through its function as a competing endogenous RNA (ceRNA) of miR-5623-3p and miR-217-5p to stimulate lipid metabolism. CONCLUSION: In this study, we have characterized ROLLCSC, a novel lncRNA, as a pivotal regulator in the metastasis of lung cancer, highlighting its potential as a therapeutic target. Specifically, we show that ROLLCSC is encapsulated by the EVs of LLC-SDs and transmitted to the LLCs, where it acts as a ceRNA of miR-5623-3p and miR-217-5p to stimulate lipid metabolism and ultimately augments metastatic colonization of LLCs.

Exosomal lncRNA Mir100hg derived from cancer stem cells enhance glycolysis and promote metastasis of lung adenocarcinoma through mircroRNA-15a-5p/31-5p.

BACKGROUND: Exosomes are a new class of molecular entities in the metastatic microenvironment, which can mediate bidirectional communication between cells. While exosomes-mediated interactions between tumor cells and other cell populations in the tumor microenvironment have attracted most attention, little is known about the significance of exosomes in mediating the interaction between non-stemness cancer cells and cancer stem cells during cancer progression. METHODS: The structure, sequence and downstream target miRNAs of lncRNA Mir100hg were predicted by online web resources. The bioinformatics prediction results were validated with experimental verification: exosome tracing, electron microscopy, Luciferase assay, metabolomics sequencing and mouse tail vein model of pulmonary metastasis. A complex regulatory network of "cancer stem cells-exosomal lncRNA-non-stem cancer cells" was constructed. RESULTS: This study demonstrates firstly that lncRNA Mir100hg is upregulated in lung cancer stem cell LLC-SD (Lung cancer stem cells) and can be delivered to non-stemness cancer cells LLC (Lewis lung cancer cells) via exosomes. In LLC, Mir100hg targets miR-15a-5p and miR-31-5p which leads to the increase of the global glycolytic activity of lung cancer cells and consequently, the enhancement of their metastatic capability. CONCLUSION: We delineated a complex regulatory network that utilized by cancer stem cells to transfer their high metastatic activity to the low-metastatic non-stemness cancer cells through exosomal Mir100hg, thereby providing new mechanistic insights into the communication between two heterogeneous tumor cells. Video Abstract.

Synergistic inhibition of NUDT21 by secretory S100A11 and exosomal miR-487a-5p promotes melanoma oligo- to poly-metastatic progression.

Although early diagnosis and therapeutic advances have transformed the living quality and outcome of cancer patients, the poor prognosis for metastatic patients has not been significantly improved. Mechanisms underlying the complexity of metastasis cannot be simply determined by the straightforward 'cause-and-effect relationships'. We have developed a 'dry-lab-driven knowledge discovery and wet-lab validation' approach to embrace the complexity of cancer and metastasis. We have revealed for the first time that polymetastatic (POL) melanoma cells can utilize both the secretory protein pathway (S100A11-Sec23a) and the exosomal crosstalk (miR-487a-5p) to transfer their 'polymetastatic competency' to the oligometastatic (OL) melanoma cells, via synergistic co-targeting of the tumor-suppressor Nudt21. The downstream deregulated glycolysis was verified to regulate metastatic colonization efficiency. Further, two gene sets conferring independent prognosis in melanoma were identified, which have the potential for clinical translation and merit future clinical validation.

Long-term outcomes of ultrasound guided high intensity focused ultrasound ablation for patients with uterine fibroids classified by T2WI: a multicenter retrospective study.

OBJECTIVE: To evaluate the long-term outcomes of ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation of uterine fibroids classified by T2-weighted magnetic resonance imaging (T2WI-MRI). MATERIALS AND METHODS: The data of 1427 premenopausal women with symptomatic uterine fibroids who underwent USgHIFU at four teaching hospitals in China were analyzed retrospectively. The uterine fibroids were classified based on their T2WI-MRI signal intensities relative to that of skeletal muscle, myometrium and endometrium as: hypointense, isointense, heterogeneous hyperintense fibroids (HHF), slightly HHF (sHHF) and markedly HHF (mHHF), respectively. The rates of symptom relief and reintervention post-USgHIFU ablation were compared between the classified groups. RESULTS: A total of 1303 patients were followed up for 44 (40, 49) months. The symptom relief rate of the hypointense and isointense fibroids was 83.3% and 79.5%, respectively, which were significantly higher (p < .05) compared to that of HHF, sHHF and mHHF (58.3%, 44.2% and 60.4%), respectively. sHHF had the lowest symptom relief rate (p < .05). The cumulative reintervention rate for hypointense, isointense, HHF, sHHF and mHHF types were 8.8%, 10.8%, 21.4%, 39.9% and 19.8%, respectively. The reintervention rate of hypointense/isointense fibroids was significantly lower than that of HHF/mHHF/sHHF (p < .01), while sHHF had the highest re-intervention rate (p < .01). Thus, reintervention rate is inversely correlated to the rate of symptom relief. CONCLUSIONS: USgHIFU ablation is effective for hypointense, isointense, HHF and mHHF with acceptable long-term follow-up outcomes. However, sHHF is associated with a higher reintervention rate.

Exosomal miR-211-5p regulates glucose metabolism, pyroptosis, and immune microenvironment of melanoma through GNA15.

Despite the unprecedented advancement of cancer treatment, the prognosis for patients with metastatic stage of cancer remains poor. The challenge that underlines this clinical dilemma is the complexity of metastasis. The conventional experiment-driven discovery approaches (the "wet lab") yield overly simplified one-to-one mechanistic relationships that are inept of elucidating the complexity of metastasis. Metastasis research also suffers from the knowledge and skill deficiency of the individual investigators. The importance of the present study is the demonstration that the "dry-lab-driven discovery and wet-lab validation" approach can improve the efficiency of studying complex biological behaviors, and can yield more reliable, objective and comprehensive mechanistic findings that are have clinical significance. Specifically, we applied this approach to study the mechanisms that underline the involvement of exosomal miRNAs in transferring the metastatic capability between heterogenous melanoma cancer cells. We show that the highly metastatic melanoma tumor cells (POL) can transfer their metastatic competency to the low-metastatic melanoma tumor cells (OL) by exosomal miR-211-5p. The oncogenic activity of miR-211-5p is mediated by the target gene guanine nucleotide-binding protein subunit alpha-15 (GNA15) through modifying the immune function of the tumor microenvironment extrinsically; as well as through inhibiting pyroptosis and augmenting glycolysis within OL cells intrinsically. In addition, we show that exosomal sorting of miR-211-5p is like selective and is subjected to regulation by a transcriptional feedback loop between miR-211-5p and zinc finger FYVE-type containing 26 (ZFYVE26). Furthermore, the "8-genes pyroptosis Risk model" derived from LASSO regression analysis was verified as an independent prognostic factor for melanoma.

Exosomal microRNA-4535 of Melanoma Stem Cells Promotes Metastasis by Inhibiting Autophagy Pathway.

High mortality rate and poor survival in melanoma are associated with efficient metastatic colonization. The underlying mechanisms remain elusive. Elucidating the role of exosomes in mediating the interactions between cancer cells and the metastatic microenvironment has been focused on cancer cell derived exosomes in modulating the functions of stromal cells. Whether cancer stem cells (CSCs) can modify the metastatic properties of non-CSC cells, and whether exosomal crosstalk plays a role have not been demonstrated prior to this report. In this study, a paired M14 melanoma derivative cell line, i.e., melanoma parental cell (MPC) and its CSC derivative cell line melanoma stem cell (MSC) were employed. We demonstrated that exosomal crosstalk betwen MSCs and non-CSC MPCs is a new mechanism that underlies melanoma metastasis. Low metastatic melanoma cells (MPCs) can acquire the "metastatic power" from highly metastatic melanoma CSCs (MSCs). We illustrated an uncharacterized microRNA, miR-4535 in mediating such exosomal crosstalk. MSCs deliver its exosomal miR-4535 to the targeted MPCs. Upon entering MPCs, miR-4535 augments metastatic colonization of MPCs by inactivating the autophagy pathway.

Melanoma stem cells promote metastasis via exosomal miR-1268a inactivation of autophagy.

BACKGROUND: Metastatic melanoma has a high mortality rate and poor survival. This is associated with efficient metastatic colonization, but the underlying mechanisms remain elusive. Communication between cancer stem cells (CSCs) and cancer cells plays an important role in metastatic dissemination. Whether cancer stem cells can alter the metastatic properties of non-CSC cells; and whether exosomal crosstalk can mediate such interaction, have not been demonstrated in melanoma prior to this report. RESULTS: The results revealed that exosomes secreted by highly metastatic melanoma CSCs (OL-SCs) promoted the invasiveness of the low metastatic melanoma cells (OL) and accelerated metastatic progression. miR-1268a was up-regulated in cells and exosomes of OL-SCs. Moreover, OL-SCs-derived exosomal miR-1268a, upon taking up by OL cells, promoted the metastatic colonization ability of OL cells in vitro and in vivo. In addition, the pro-metastatic activity of exosomal miR-1268a is achieved through inhibition of autophagy. CONCLUSION: Our study demonstrates that OL cells can acquire the "metastatic ability" from OL-SCs cells. OL-SCs cells achieves this goal by utilizing its exosomes to deliver functional miRNAs, such as miR-1268a, to the targeted OL cells which in turn augments metastatic colonization by inactivating the autophagy pathway in OL cells.

Extracellular vesicles microRNA-592 of melanoma stem cells promotes metastasis through activation of MAPK/ERK signaling pathway by targeting PTPN7 in non-stemness melanoma cells.

Melanoma, one of the most aggressive malignancies, its high mortality and low survival rates are associated with effective metastatic colonization. Melanoma metastasis hinges on the bidirectional cell-cell communication within the complex metastatic microenvironments (MME). Extracellular vesicles (EVs) are recognized as a new class of molecular mediator in MME programing. Published studies show that melanoma EVs can educate MME stromal cells to acquire the pro-metastatic phenotype to enhance metastatic colonization. Whether EVs can mediate the interactions between heterogenous cancer cells within the MME that alter the course of metastasis has not been investigated at the mechanistic level. In this study, melanoma parental cells (MPCs) and paired derivative cancer stem cell line melanoma stem cells (MSCs) that were derived from melanoma cell line M14 were used. We demonstrate that the EVs-mediated crosstalk between the MSCs and the MPCs is a novel mechanism for melanoma metastasis. We characterized miR-592, a relatively novel microRNA of prognostic potential, in mediation of such intercellular crosstalk. EVs can encapsulate and deliver miR-592 to target MPCs. Upon entering, miR-592 inhibits the expression of its gene target protein tyrosine phosphatase non-receptor type7 (PTPN7), a phosphatase targeting MAPKs. This leads to the relief of the inhibitory effect of PTPN7 on MAPK/ERK signaling and consequently the augmentation of metastatic colonization of MPCs. Thus, via the extracellular vesicle miR-592/PTPN7/MAPK axis, melanoma-CSCs can transfer their metastatic ability to the low-metastatic non-CSC melanoma cells.

High-Metastatic Melanoma Cells Promote the Metastatic Capability of Low-Metastatic Melanoma Cells via Exosomal Transfer of miR-411-5p.

Melanoma is characterized by high rate of metastasis and mortality. Effective management of metastatic melanoma depends on renewed mechanistic understanding underlying melanoma progression and metastasis. The role of exosomes in mediating the interactions between cancer cells and the metastatic microenvironment is at the forefront of cancer research. Previous researches on the function of exosomes in metastasis have been primarily focused on tumor cell-derived exosomes in modifying the biological functions of stromal cells. Whether the cancer cells at the involved organ can modify the metastatic capability of each other has not been demonstrated. In this study, a paired M14 melanoma derivative cell line, i.e., M14-OL and POL, that we established and characterized were employed. Oligo-metastatic (M14-OL) and poly-metastatic (M14-POL) cell line were generated from three consecutive rounds of in vivo selection and passage. They exhibit high (POL cells) and low (OL cells) metastatic colonization efficiency in vivo, respectively. We show that exosomal crosstalk between metastatic cancer cells is a new mechanism of cancer metastasis. High-metastatic melanoma cells (POL) can augment the metastatic colonization capability of the low-metastatic melanoma cells (OL). POL achieves this goal by utilizing its exosomes to deliver functional miRNAs, in this case, miR-411-5p, to the OL cell. Upon entering OL cells, exosomal miR-411-5p enhance metastatic colonization efficiency by activation of the ERK signaling pathway. Moreover, miR-411-5p expression is higher in cancer tissues of other cancer types (colon, lung, rectum) compared with that of respective normal tissues. The clinical relevance of the present finding merits future investigations.

Corrigendum to "Identification and characterization of the cellular subclones that contribute to the pathogenesis of mantle cell lymphoma" [Genes Dis 6(4) 2019 407-418].

[This corrects the article DOI: 10.1016/j.gendis.2018.12.002.].

Melanoma stem cells promote metastasis via exosomal miR-1268a inactivation of autophagy

BACKGROUND: Metastatic melanoma has a high mortality rate and poor survival. This is associated with efficient metastatic colonization, but the underlying mechanisms remain elusive. Communication between cancer stem cells (CSCs) and cancer cells plays an important role in metastatic dissemination. Whether cancer stem cells can alter the metastatic properties of non-CSC cells; and whether exosomal crosstalk can mediate such interaction, have not been demonstrated in melanoma prior to this report. RESULTS: The results revealed that exosomes secreted by highly metastatic melanoma CSCs (OL-SCs) promoted the invasiveness of the low metastatic melanoma cells (OL) and accelerated metastatic progression. miR-1268a was up-regulated in cells and exosomes of OL-SCs. Moreover, OL-SCs-derived exosomal miR-1268a, upon taking up by OL cells, promoted the metastatic colonization ability of OL cells in vitro and in vivo. In addition, the pro-metastatic activity of exosomal miR-1268a is achieved through inhibition of autophagy. CONCLUSION: Our study demonstrates that OL cells can acquire the "metastatic ability" from OL-SCs cells. OL-SCs cells achieves this goal by utilizing its exosomes to deliver functional miRNAs, such as miR-1268a, to the targeted OL cells which in turn augments metastatic colonization by inactivating the autophagy pathway in OL cells.

SEC23A Is an Independent Prognostic Biomarker in Bladder Cancer Correlated With MAPK Signaling.

Clinical data mining and bioinformatics analysis can be employed effectively to elucidate the function and underlying mechanisms of the gene of interest. Here, we have proposed a framework for the identification and validation of independent biomarkers in human cancer and for mechanistic profiling using gene sets enrichment analysis and pathway analysis. This is followed by validation with in vitro experiments. Using this framework to analyze the clinical relevance of SEC23A, we have discovered the prognostic potential of SEC23A in different cancers and identified SEC23A as an independent prognostic factor for poor prognosis in bladder cancer, which implicates SEC23A, for the first time, as an oncogene. Bioinformatic analyses have elucidated an association between SEC23A expression and the upregulation of the MAPK signaling pathway. Using the T24 human bladder cell line, we confirmed that knockdown of SEC23A expression could effectively impact the MAPK signaling pathway. Further, through PCR verification, we showed that MEF2A, one of the key genes of the MAPK signaling pathway, might be a downstream factor of the SEC23A gene.

SEC23A Inhibit Melanoma Metastatic through Secretory PF4 Cooperation with SPARC to Inhibit MAPK Signaling Pathway.

Metastasis of melanoma to the distant organs is a multistep process in which the tumor microenvironment (TME) may play an important role. However, the relationship between metastatic progression and TME is intricate. In the present study, using melanoma derivative cell lines OL (oligometastatic) and POL (polymetastatic) that differ in their metastatic colonization capability, we have elucidated a new mechanism involving "SEC23A-PF4-MAPK/ERK axis" in which PF4 transported by COPII hinders metastasis through inhibition of MAPK/ERK signaling pathway. Furthermore, SPARC can act cooperatively to enhance the inhibition of Pf4 on ERK phosphorylation and melanoma cell metastasis. Our findings show the possibility of targeting cancer cell secretome for therapeutic development.

Characteristics of the PI3K/AKT and MAPK/ERK pathways involved in the maintenance of self-renewal in lung cancer stem-like cells.

Lung cancer is the leading cause of cancer-related mortality worldwide due to its early asymptomatic and late metastasis. While cancer stem cells (CSCs) may play a vital role in oncogenesis and development of lung cancer, mechanisms underlying CSCs self-renewal remain less clear. In the present study, we constructed a clinically relevant CSCs enrichment recognition model and evaluated the potential functions of phosphatidylinositol 3-kinase (PI3K)/AKT pathway (PI3K/AKT) and mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathways in lung cancer via bioinformatic analysis, providing the basis for in depth mechanistic inquisition. Experimentally, we confirmed that PI3K/AKT pathway predominantly promotes proliferation through anti-apoptosis in lung adenocarcinoma cells, while MAPK/ERK pathway has an overwhelming superiority in regulating the proliferation in lung CSCs. Further, utilizing stemness score model, LLC-Symmetric Division (LLC-SD) cells and mouse orthotopic lung transplantation model, we elucidated an intricate cross-talk between the oncogenic pathway and the stem cell reprograming pathway that impact stem cell characteristics as well as cancer biology features of lung CSCs both in vitro and in vivo. In summary, our findings uncovered a new insight that PI3K/AKT and MAPK/ERK pathways as oncogenic signaling pathway and/or stem cell signaling pathway act distinctively and synergistically to regulate lung CSCs self-renewal.

Cdh1 functions as an oncogene by inducing self-renewal of lung cancer stem-like cells via oncogenic pathways.

The mortality rate of lung cancer remains the highest amongst all cancers despite of new therapeutic developments. While cancer stem cells (CSCs) may play a pivotal role in cancer, mechanisms underlying CSCs self-renewal and their relevance to cancer progression have not been clearly elucidated due to the lack of reliable and stable CSC cellular models. In the present study, we unveiled the novel oncogene function of cadherin 1 (Cdh1) via bioinformatic analysis in a broad spectrum of human cancers including lung adenocarcinoma (LUAD), adding a new dimension to the widely reported tumor suppressor function of Cdh1. Experimentally, we show for the first time that Cdh1 promotes the self-renewal of lung CSCs, consistent with its function in embryonic and normal stem cells. Using the LLC-Symmetric Division (LLC-SD) model, we have revealed an intricate cross-talk between the oncogenic pathway and stem cell pathway in which Cdh1 functions as an oncogene by promoting lung CSC renewal via the activation of the Phosphoinositide 3-kinase (PI3K) and inhibition of Mitogen-activated protein kinase (MAPK) pathways, respectively. In summary, this study has provided evidence demonstrating effective utilization of the normal stem cell renewal mechanisms by CSCs to promote oncogenesis and progression.

Identification and characterization of the cellular subclones that contribute to the pathogenesis of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a B-cell malignancy with poor clinical outcome and undefined pathogenesis. Development of clinically relevant cellular models for MCL research is an urgent need. Our preliminary observations lead the development of two novel hypotheses that we tested in this study: 1. multicellular spheroid might be a unique growth mode of early-stage cells in MCL; 2. MCL might be a polyclonal tumor. We made the following original observations that have not been reported: First, we have provided a new experiment method for enriching MCL early-stage cells and characterized the spheroid mode of growth as a unique feature of early-stage MCL cells in cell line as well as in clinical samples. Second, we have established a clinically relevant cellular model of MCL, the JeKo-1-spheroid cell line, that was highly enriched in early-stage sub-clones. JeKo-1-spheroid cells and the spheroid growing cells enriched from MCL patients exhibited comparably enhanced tumorigenic abilities and similar biological features. Third, Immunophenotypic analysis has revealed that MCL may be derived from precursor-B(pre-B), immature-B and mature-B cells, not only the mature-B cells as WHO classified in 2016. Fourth, MCL may be a polyclonal disease composed of CD19-/IgM-, CD19-/IgM+, CD19+/IgM+ three sub-clones, of which the CD19-/IgM+ sub-clone might be the dominant sub-clone with the strongest tumorigenic ability. Fifth, CD19+/IgM- that differentiates MCL and normal B cells may represent a new marker for MCL early detection, minor residual disease monitoring after therapies and prognosis.

Asymmetric Division Gene Neurl2 Mediates Twist2 Regulation of Self-Renewal of Mouse Lewis Lung Cancer Stem Cells.

Cancer stem cells (CSCs) play an important role in tumor development. While Epithelial-Mesenchymal Transition (EMT) has been shown to promote CSC self-renewal, underlying mechanisms are unclear. Here we identified and characterized the requirement of twist2, the EMT transcription factor, for the regulation of self-renewal thus stemness of mouse Lewis lung CSCs both in vitro and in vivo. Further, we elucidated the role of neurl2, an asymmetric division gene for normal stem cells, in mediating the self-renewal promoting activity of twist2. Moreover, analysis of TCGA showed a positive correlation between the expression of twist2 and the development of lung adenocarcinoma, and a negative correlation between neurl2 and lung adenocarcinoma development. In summary, our study provides a new mechanistic insight of regulation of CSC self-renewal by EMT.