Mesenchymal stromal cells affect cardiomyocyte growth through juxtacrine Notch-1/Jagged-1 signaling and paracrine mechanisms: clues for cardiac regeneration

The possibility to induce myocardial regeneration by the activation of resident cardiac stem cells (CSCs) has raised great interest. However, to propose endogenous CSCs as therapeutic options, a better understanding of the complex mechanisms controlling heart morphogenesis is needed, including the cellular and molecular interactions that cardiomyocyte precursors establish with cells of the stromal compartment. In the present study, we co-cultured immature cardiomyocytes from neonatal mouse hearts with mouse bone marrow-derived mesenchymal stromal cells (MSCs) to investigate whether these cells could influence cardiomyocyte growth in vitro. We found that cardiomyocyte proliferation was enhanced by direct co-culture with MSCs compared with the single cultures. We also showed that the proliferative response of the neonatal cardiomyocytes involved the activation of Notch-1 receptor by its ligand Jagged-1 expressed by the adjacent MSCs. In fact, the cardiomyocytes in contact with MSCs revealed a stronger immunoreactivity for the activated Notch-intracellular domain (Notch-ICD) as compared with those cultured alone and this response was significantly attenuated when MSCs were silenced for Jagged-1. The presence of various cardiotropic cytokines and growth factors in the conditioned medium of MSCs underscored the contribution of paracrine mechanisms to Notch-1 up-regulation by the cardiomyocytes. In conclusions these findings unveil a previously unrecognized function of MSCs in regulating cardiomyocyte proliferation through Notch-1/Jagged-1 pathway and suggest that stromal-myocardial cell juxtacrine and paracrine interactions may contribute to the development of new and more efficient cell-based myocardial repair strategies.     

Microenvironment of mammary fat pads affected the characteristics of the tumors derived from the induced cancer stem cells

Breast cancer is the first common cause of cancer-related death in women worldwide. Since the malignancy and aggressiveness of breast cancer have been correlated with the presence of breast cancer stem cells, the establishment of a disease model with cancer stem cells is required for the development of a novel therapeutic strategy. Here, we aimed to evaluate the availability of cancer stem cell models developed from mouse induced pluripotent stem cells with the conditioned medium of different subtypes of breast cancer cell lines, the hormonal-responsive T47D cell line and the triple-negative breast cancer BT549 cell line, to generate in vivo tumor models. When transplanted into the mammary fat pads of BALB/c nude mice, these two model cells formed malignant tumors exhibiting pronounced histopathological characteristics similar to breast cancers. Serial transplantation of the primary cultured cells into mammary fat pads evoked the same features of breast cancer, while this result was perturbed following subcutaneous transplantation. The tumors formed in the mammary fat pads exhibited immune reactivities to prolactin receptor, progesterone receptor, green florescent protein, Ki67, CD44, estrogen receptor α/β and cytokeratin 8, while all of the tumors and their derived primary cells exhibited immunoreactivity to estrogen receptor α/β and cytokeratin 8. Cancer stem cells can be developed from pluripotent stem cells via the secretory factors of cancer-derived cells with the capacity to inherit tissue specificity. However, cancer stem cells should be plastic enough to be affected by the microenvironment of specific tissues. In summary, we successfully established a breast cancer tumor model using mouse induced pluripotent stem cells developed from normal fibroblasts without genetic manipulation.     

Embryonic signature in breast cancers; Pluripotency roots of cancer stem cells

Drug discovery programs for preclinical oncology typically select compounds which have a predilection for inducing cytotoxic effects in cancer cell lines and subsequently, for inhibiting the growth of the transplanted cancer cells in vivo (Winquist et al., 2010). Unfortunately, the cytotoxic effect in vitro and inhibition of tumor growth in animal models are not the end story for curing cancer in preclinical models. The reason behind that is the exciting of small sub type of cells that are relatively resistance to therapy and able to repopulate in vivo, called cancer stem cells (CSCs). O leis et al. recently reported that the pluripotency gene Sox2 but not Oct4 or Nanog is expressed in early stage of breast tumor. Furthermore, the authors demonstrated that Sox2 downregulation, inhibited mammosphere formation and delayed tumor formation in xenograft tumor initiation models (Leis et al., 2012). In this review, we will shed the light on the importance of Sox2 in breast and other tissue tumorigenesis and associated aggressiveness.     

EMT,CTCs and CSCs in tumor relapse and drug-resistance

Tumor relapse and metastasis are the primary causes of poor survival rates in patients with advanced cancer despite successful resection or chemotherapeutic treatment. A primary cause of relapse and metastasis is the persistence of cancer stem cells (CSCs), which are highly resistant to chemotherapy. Although highly efficacious drugs suppressing several subpopulations of CSCs in various tissue-specific cancers are available, recurrence is still common in patients. To find more suitable therapy for relapse, the mechanisms underlying metastasis and drug-resistance associated with relapse-initiating CSCs need to be identified. Recent studies in circulating tumor cells (CTCs) of some cancer patients manifest phenotypes of both CSCs and epithelial-mesenchymal transition (EMT). These patients are unresponsive to standard chemotherapies and have low progression free survival, suggesting that EMT-positive CTCs are related to co-occur with or transform into relapse-initiating CSCs. Furthermore, EMT programming in cancer cells enables in the remodeling of extracellular matrix to break the dormancy of relapse-initiating CSCs. In this review, we extensively discuss the association of the EMT program with CTCs and CSCs to characterize a subpopulation of patients prone to relapses. Identifying the mechanisms by which EMT-transformed CTCs and CSCs initiate relapse could facilitate the development of new or enhanced personalized therapeutic regimens.     

肿瘤干细胞在卵巢癌治疗中的进展

卵巢恶性肿瘤是死亡率最高的妇科恶性肿瘤。尽管标准化的治疗方法（包括理想的肿瘤细胞减灭术和以铂类／紫杉醇为基础的化疗方案）使得70％的患者得到一定程度的临床缓解,但绝大多数患者仍然会在2年内复发并出现耐药。肿瘤干细胞理论认为,肿瘤组织中有小部分细胞群体具有极强的增殖能力,它们具有类似正常干细胞的生物学特性,能通过自我更新和分化来高频度地启动肿瘤的发生发展,它们是导致肿瘤发生、发展、转移和耐药的主要细胞,是肿瘤复发的根源。该文将概述近几年卵巢癌干细胞的各项研究,包括卵巢癌干细胞的分离及其耐药机制、各种治疗方法等。     

Human heart failure: Is cell therapy a valid option?

The concept of the heart as a terminally differentiated organ incapable of replacing damaged myocytes has been at the center of cardiovascular research and therapeutic development for the past 50 years. The progressive decline in myocyte number with aging and the formation of scarred tissue following myocardial infarction have been interpreted as irrefutable proofs of the post-mitotic characteristics of the adult heart. However, emerging evidence supports a more dynamic view of the myocardium in which cell death and cell restoration are vital components of the remodeling process that governs organ homeostasis, aging and disease. The identification of dividing myocytes throughout the life span of the organisms and the recognition that undifferentiated primitive cells regulate myocyte turnover and tissue regeneration indicate that the heart is a self-renewing organ controlled by a compartment of resident stem cells. Moreover, exogenous progenitors of bone marrow origin transdifferentiate and acquire the cardiomyocyte and vascular lineages. This new reality constitutes the foundation of the numerous cell-based clinical trials that have been conducted in the last decade for the treatment of ischemic and non-ischemic cardiomyopathies.     

肿瘤干细胞及其niche的中医属性及发生病机

认为肿瘤干细胞（CSCs）是深藏于癌毒微环境中癌毒产生之根本原因,是肿瘤复发、转移的根源。有别于正常干细胞niche封藏、守位之特征,CSCs居于正气亏虚肿瘤微环境的至虚之处,容留CSCs的niche以虚为本,兼具瘀与痰之特征。CSCs属于离位之相火妄动,元气益虚而毒根愈固。提出通过扶正来干预CSCs及其赖以生存之niche,从根本上改善微环境之虚与瘀,可能是拔除肿瘤毒根的有效策略。<     

Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol

Present study shows that drug resistant human breast cancer cells are enriched in cancer stem-like cells (CSCs) and express elevated levels of Stat-3 signaling mediators, which contribute to CSC enrichment. Simvastatin (SVA) and gamma-tocotrienol (γT3) eliminate enriched CSCs and suppress expression of Stat-3 signaling mediators via inhibition of the mevalonate pathway and activation of de novo ceramide synthesis pathway, respectively. Combination of SVA + γT3 at low doses enhanced these actions via inhibition of the mevalonate pathway. Data demonstrate that SVA and γT3 alone or in combination possess the ability to eliminate CSCs in drug resistant human breast cancer cells.