Implications of Stem Cells and Cancer Stem Cells for Understanding Fomation and Therapy of Cancer

Most cancers are heterogeneous with respect to proliferation and differentiation. There is increasing evidence suggesting that only a minority of cancer cells, tumorigenic or tumor initiating cells, possess the capacity to proliferate extensively and form new hematopoietic cancer or solid tumors. Tumor initiating cells share characteristics required for normal stem cells. The dysregulation of self-renewal and proliferation of stem cells is a likely requirement for cancer development. This review formulates a model for the origin of cancer stem cells and regulating self-renewal which influences the way we study and treat cancer.     

Pancreatic cancer stem cells: implications for the treatment of pancreatic cancer

Pancreatic cancer is a highly lethal disease that is usually diagnosed at a late stage for which there are few effective therapies. Emerging evidence has suggested that malignant tumors are quite heterogeneous and that they are composed of a small subset of distinct cancer cells (usually defined by cell surface marker expression) that are responsible for tumor initiation and propagation, termed cancer stem cells. These cells are termed cancer stem cells because, like normal stem cells, they possess the ability to self-renew and make differentiated progeny. Recent studies of human pancreatic cancers have shown a population of pancreatic cancer stem cells that have aberrantly activated developmental signaling pathways, are resistant to standard chemotherapy and radiation, and have up-regulated signaling cascades that are integral for tumor metastasis. An improved understanding of the biological behavior of these cells may lead to more effective therapies to treat pancreatic cancer. In this review, approaches to develop and test therapeutics targeting pancreatic cancer stem cells are discussed.     

肝癌干细胞的分选和治疗进展

肿瘤干细胞学说是目前的研究热点,多项研究表明在人类实体瘤中存在肿瘤干细胞,而干细胞数量在肿瘤细胞中含量极少,目前没有特异性肿瘤表面标志物能对肿瘤干细胞进行分选,所以如何有效分离肿瘤干细胞及干预其生长是目前值得研究的课题,本文就肝癌干细胞的表面标志物、分选方法、治疗及存在的问题做一综述。     

Epithelial-mesenchymal transition,cancer stem cells and treatment resistance

Breast cancer relapse, in a large number of patients, after initial response to standard of care therapy warrants development of novel therapies against recurrent and metastatic cancer. Cancer stem cells (CSCs), present in breast tumors while being intrinsically resistant to conventional therapy, have the ability to self renew and cause tumor recurrence. The residual tumors after therapy, with dramatic enrichment of the CSCs, have all the hallmarks of epithelial- mesenchymal transition (EMT). This review will focus on the link between EMT, CSCs and treatment resistance, since a better understanding of these interactions will allow us to effectively target the residual population after therapy.     

乳腺干细胞和乳腺癌干细胞研究现状

<正>干细胞是机体内具有自我更新和多向分化潜能的细胞群体,并能通过分化产生特定组织的成熟细胞,理论上一个干细胞可以发育成为完整的生物个体或组织器官[1]。关于干细胞的概念,目前最广泛接受的是,干细胞是可以进行对称和非对称分裂的未分化的细胞群:分裂发生时,一个干细胞产生两个子细胞,一个与母细胞完全一致,具有母细胞同样的特征;另一个细胞可以分化形成不同的成熟细胞株。     

Tumour stem cells: the biological concept and its application in cancer treatment

Experiments in different transplantable mouse tumours suggest that a proportion ranging from 0.1% to 100% of all tumour cells in these different tumours meet the functional definition criteria of tumour stem cells, i.e. regrowth of the tumour proceeded by clonal expansion from a single cell with unlimited proliferative potential. It is concluded that the proliferative organization of many or most human tumours may resemble that of the tissue of origin with a small proportion of stem cells and the majority of transit cells, both proliferating or resting. Cell loss and accelerated repopulation are due to regulated changes in the symmetry constraint of stem cell divisions.     

肿瘤干细胞及其对肿瘤治疗理念的影响

肿瘤干细胞是医学生物学和生命科学研究的前沿课题,也是研究的热点,它与肿瘤的发生及治疗有着密切关系.干细胞是一类具有自我更新能力、高度增殖和多向分化潜能的细胞群.它们可以通过对称性分裂维持自身细胞群的数量,同时又可以进一步分化成为各种不同的组织细胞,从而构成机体各种复杂的组织和器官~([1]).     

Normal stem cells and cancer stem cells: the niche matters

Scientists have tried for decades to understand cancer development in the context of therapeutic strategies. The realization that cancers may rely on "cancer stem cells" that share the self-renewal feature of normal stem cells has changed the perspective with regard to new approaches for treating the disease. In this review, we propose that one of the differences between normal stem cells and cancer stem cells is their degree of dependence on the stem cell niche, a specialized microenvironment in which stem cells reside. The stem cell niche in adult somatic tissues plays an essential role in maintaining stem cells or preventing tumorigenesis by providing primarily inhibitory signals for both proliferation and differentiation. However, the niche also provides transient signals for stem cell division to support ongoing tissue regeneration. The balance between proliferation-inhibiting and proliferation-promoting signals is the key to homeostatic regulation of stem cell maintenance versus tissue regeneration. Loss of the niche can lead to loss of stem cells, indicating the reliance of stem cells on niche signals. Therefore, cancer stem cells may arise from an intrinsic mutation, leading to self-sufficient cell proliferation, and/or may also involve deregulation or alteration of the niche by dominant proliferation-promoting signals. Furthermore, the molecular machinery used by normal stem cells for homing to or mobilizing from the niche may be "hijacked" by cancer stem cells for invasion and metastasis. We hope this examination of the interaction between stem cells and their niche will enhance understanding of the process of cancer development, invasiveness, and metastasis and reveal possible targets for cancer treatment.     

Revisiting the concept of cancer stem cells in prostate cancer

The cancer stem cell (CSC) model proposes that cells within a tumor are organized in a hierarchical lineage relationship and display different tumorigenic potential, suggesting that effective therapeutics should target rare CSCs that sustain tumor malignancy. Here we review the current status of studies to identify CSCs in human prostate cancer as well as mouse models, with an emphasis on discussing different functional assays and their advantages and limitations. We also describe current controversies regarding the identification of prostate epithelial stem cells and cell types of origin for prostate cancer, and present potential resolutions of these issues. Although definitive evidence for the existence of CSCs in prostate cancer is still lacking, future directions pursuing the identification of tumor-initiating stem cells in the mouse may provide important advances in evaluating the CSC model for prostate cancer.     

Breast cancer stem cells: treatment resistance and therapeutic opportunities

The clinical and pathologic heterogeneity of human breast cancer has long been recognized. Now, molecular profiling has enriched our understanding of breast cancer heterogeneity and yielded new prognostic and predictive information. Despite recent therapeutic advances, including the HER2-specific agent, trastuzumab, locoregional and systemic disease recurrence remain an ever-present threat to the health and well being of breast cancer survivors. By definition, disease recurrence originates from residual treatment-resistant cells, which regenerate at least the initial breast cancer phenotype. The discovery of the normal breast stem cell has re-ignited interest in the identity and properties of breast cancer stem-like cells and the relationship of these cells to the repopulating ability of treatment-resistant cells. The cancer stem cell model of breast cancer development contrasts with the clonal evolution model, whereas the mixed model draws on features of both. Although the origin and identity of breast cancer stem-like cells is contentious, treatment-resistant cells survive and propagate only because aberrant and potentially druggable signaling pathways are recruited. As a means to increase the rates of breast cancer cure, several approaches to specific targeting of the treatment-resistant cell population exist and include methods for addressing the problem of radioresistance in particular.     

肺癌干细胞

现有研究表明,在肺癌中与干细胞功能相关的Wnt、Notch和Hedgehog信号通路被异常激活,它们与肺癌干细胞的高致瘤性、高转移性、耐药性等特性密切相关.多项研究显示肺癌干细胞群高度表达肿瘤耐药蛋白并且对放化疗明显耐受.因此,如何靶向治疗肺癌干细胞,最终根治肺癌,正逐渐成为肿瘤靶向治疗研究中的热点.     

肺癌干细胞

现有研究表明,在肺癌中与于细胞功能相关的wnt、Notch和Hedgehog信号通路被异常激活,它们与肺癌干细胞的高致瘤性、高转移性、耐药性等特性密切相关。多项研究显示肺癌干细胞群高度表达肿瘤耐药蛋白并且对放化疗明显耐受。因此,如何靶向治疗肺癌干细胞,最终根治肺癌,正逐渐成为肿瘤靶向治疗研究中的热点。     

小白菊内酯体内杀伤小鼠乳腺癌肿瘤干细胞

目的： 探讨小白菊内酯（parthenolide,PTL）对小鼠乳腺癌肿瘤干细胞（cancer stem cell,CSC）的杀伤作用,为临床应用PTL治疗乳腺癌提供实验依据。 方法： 采用5-氟尿嘧啶（5-fluorouracil, 5-FU）化疗法制备富含CSC的小鼠4T1细胞乳腺癌模型,随机分为对照组、5-FU组、PTL组。4周后脱颈处死小鼠,检测各组小鼠肿瘤的体积和重量,流式细胞术检测小鼠肿瘤组织中CD44+CD24-/low细胞比例,Hoechst33342染色法检测侧群（side population,SP）细胞的比例,免疫组化法检测CD55和乙醛脱氢酶1（aldehyde dehydrogenase1,ALDH1）蛋白的表达,倒置显微镜观察乳腺癌细胞微球体的形成。 结果： 成功制备富含CSC的小鼠乳腺癌细胞移植瘤模型,PTL可下调小鼠肿瘤组织中CD44+CD24-/low细胞的比例\[（42.5±3.7）% vs （68.7±32）%,P<0.05\],有效降低荷瘤小鼠肿瘤组织中SP细胞的比例\[（39.2±1.8）% vs （61.3±2.6）%,P<0.05\],下调小鼠移植瘤组织中CD55和ALDH1蛋白的表达\[（18.9±1.5）% vs （30.1±1.3）%,（8.1±2.3）% vs （18.0±1.4）%;均P<0.05\],抑制小鼠肿瘤细胞在无血清培养条件下形成微球体,并可抑制小鼠移植瘤的体积和重量\[（0.625±0.159）cm3 vs （1.715±0184）cm3,（1.467±0.373）g vs （3.367±0.398）g;均P<0.05\]。 结论： PTL在荷瘤小鼠体内可以明显降低肿瘤组织CSC含量,提示PTL可用来靶向杀伤乳腺癌CSC。     

Breast cancer stem cells

Since the initial discovery of leukemia stem cells nearly a decade ago, a great deal of cancer research has focused on the identification of cancer stem cells (CSCs) in many types of solid tumors, including breast cancer. Through analysis of cell surface markers and xenotransplant models, a subpopulation of putative human breast cancer stem cells (BCSCs) that is CD24-negative/CD44-positive (CD24⁻/CD44⁺) and bears high aldehyde dehydrogenase 1 activity has been isolated in clinical samples of breast cancer tissues. Human BCSCs are considered to be derived from basal cells that reside in the basal membranes of alveolar units in human adult mammary glands. Furthermore, BCSCs have been shown to express higher levels of oxidative stress-responsive genes, which could confer part of their ability to resist anti-cancer therapy, than non-CSCs. The emerging picture of the biological properties of BCSCs would contribute for devising innovative therapies for breast cancer, targeting the intrinsic and extrinsic factors that maintain the BCSCs.     

Prostate cancer stem cells

Stem cells have long been implicated in prostate gland formation. The prostate undergoes regression after androgen deprivation and regeneration after testosterone replacement. Regenerative studies suggest that these cells are found in the proximal ducts and basal layer of the prostate. Many characteristics of prostate cancer indicate that it originates from stem cells. For example, the putative androgen receptor-negative (AR(-)) status of prostate stem cells renders them inherently insensitive to androgen blockade therapy. The androgen-regulated gene fusion TMPRSS2-ERG could be used to clarify both the cells of origin and the evolution of prostate cancer cells. In this review, we show that the hypothesis that distinct subtypes of cancer result from abnormalities within specific cell types-the stem cell theory of cancer-may instigate a major paradigm shift in cancer research and therapy. Ultimately, the stem cell theory of cancers will affect how we practice clinical oncology: our diagnosis, monitoring, and therapy of prostate and other cancers.     

Pancreatic cancer stem cells

Studies are emerging in support of the cancer stem cells (CSCs) theory which considers that a tiny subset of cancer cells is exclusively responsible for the initiation and malignant behavior of a cancer. This cell population, also termed CSCs, possesses the capacity both to self-renew, producing progeny that have the identical tumorigenic potential, and to differentiate into the bulk of cancer cells, helping serve the formation of the tumor entities, which, altogether, build the hierarchically organized structure of a cancer. In this review, we try to articulate the complicated signaling pathways regulating the retention of the characteristics of pancreatic CSCs, and in the wake of which, we seek to offer insights into the CSCs-relevant targeted therapeutics which are, in the meantime, confronted with bigger challenges than ever.     

Prostate cancer stem cells

Prostate cancer is the most frequently diagnosed cancer in men. Despite recent advances in the detection of early prostate cancer there is little effective therapy for patients with locally advanced and/or metastatic disease. The majority of patients with advanced disease respond initially to androgen ablation therapy. However, most go on to develop androgen-independent tumours that inevitably are fatal. A similar response is seen to chemotherapeutic and radiotherapy treatments. As a result, metastatic prostate cancer remains an incurable disease by current treatment strategies. Recent reports of cancer stem cells have prompted questions regarding the involvement of normal stem/progenitor cells in prostate tumour biology, their potential contribution to the tumour itself and whether they are the cause of tumour initiation and progression. Although still controversial, the cancer stem cell is likely to be the most crucial target in the treatment of prostate cancer, and a thorough understanding of its biology, particularly of how the cancer stem cell differs from the normal stem cell, might allow it to be targeted selectively and eliminated, thus improving therapeutic outcome.     

Complexity of cancer stem cells

Heterogeneity of tumor tissue has been accounted for in recent years by a hierarchy‐based model in which cancer stem cells (CSCs) have the ability both to self‐renew and to give rise to differentiated tumor cells and are responsible for the overall organization of a tumor. Research into CSCs has progressed rapidly and concomitantly with recent advances in the biology of normal tissue stem cells, resulting in the identification of CSCs in a wide range of human tumors. Studies of mouse models of human cancer have provided further insight into the characteristics of CSCs as well as a basis for the development of novel therapies targeted to these cells. However, recent studies have revealed complexities, such as plasticity of stem cell properties and clonal diversity of CSCs, in certain tumor types that have led to revision of the original CSC model. In this review, we summarize the history of the discovery and characterization of CSCs, as well as address recent advances that have revealed the complexity of these cells and their therapeutic implications.