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The cancer stem cell theory elucidates not only the issue of tumour initiation and development, tumour’s ability to metastasise and reoccur, but also the ineffectiveness of conventional cancer therapy. This review examines stem cell properties, such as self-renewal, heterogeneity, and resistance to apoptosis. The ‘niche’ hypothesis is presented, and mechanisms of division, differentiation, self-renewal and signalling pathway regulation are explained. Epigenetic alterations and mutations of genes responsible for signal transmission may promote the formation of cancer stem cells. We also present the history of development of the cancer stem cell theory and discuss the experiments that led to the discovery and confirmation of the existence of cancer stem cells. Potential clinical applications are also considered, including therapeutic models aimed at selective elimination of cancer stem cells or induction of their proper differentiation.
Content available remote Stem cells as a two edged sword - from regeneration to tumor formation
Evidence has accumulated that quiescent stem cells or cells developmentally closely related to them distributed in various organs may be a cellular origin of cancer development. In support of this notion, stem cells (SC) are long-lived cells with distinctive properties of self-renewal and has the potential to proliferate extensively. Given these features, it’s possible that they may become the subject of consecutive accumulated mutations that are crucial for initiation of cancer. Therefore, mutations that occur in normal stem cells might lead to their malignant transformation and tumor initiation. Furthermore, many biological features of normal and cancer SC such as the physiological trafficking of normal and metastasis of cancer stem cells involve similar molecular mechanisms, and we discuss these similarities here.
Cancer stem cells are a small subset of cancer cells constituting a reservoir of self-sustaining cells with the exclusive ability to self-renew and maintain the tumor. These cells are identified by specific stem cell markers: antigens, molecules and signaling pathways. Transcription factors and molecules associated with oncogenesis, such as NF-κB, Bmi-1, Notch, WNT beta-catenin, Sonic hedgehog and their biochemical pathways, active only in a small minority of cancer cells might play key roles in determining the biology and the overall long-term behavior of a tumor. The molecules and pathways specific for cancer stem cells, which contribute to their drug resistance, are potential targets for new therapeutic strategies.
It is generally accepted that chronic inflammatory disease, either local or generalized, is associated with higher incidence of cancer. Since inflammation is often accompanied by oxidative stress the latter was indicated as the foundation for progressive mutations leading to tumor development (proliferation, invasion, metastasis). Even though, it is very hard to demonstrate by in vitro studies the causal relationship between oxidative stress and cell transformations. From our studies it is clear that cells are more likely to stop divisions and they commit suicide by apoptosis. During last decade, a novel view on the origin of cancer emerged. The so called cancer stem cells (CSC) were found that form the side-population of stem cells (SC) and they are believed to initiate cancer. Are the SC ancestors for CSC? Do SC transform into CSC? These and other questions remain unanswered. We hypothesize that SC might undergo transformation into CSC during prolonged oxidative stress. We claim that several changes in cell biochemistry has to occur to start the molecular modifications leading to neoplasma. These include either hypoxia-promoted apoptosis signal inducing kinase 1 (ASK-1), hypoxia inducing factor 1 alpha (HIF-la) and glycolysis, or normoxia-promoted activating protein-1 (AP-1) or hyperoxia-induced nuclear factor kappa B (NF-kB). Next, harsh microenviron- ment and heterogenous extracellular matrix (ECM) induced by oxidative stress accelerate the selection of clones of cells resistant to apoptogenic signal. HIF-la, protein crucial for transcriptional activation of protooncogene met leads to the overexpression of c-Met receptor that in turn sensitizes cells to hepatocyte growth factor/scatter factor (HGF/SF) mitogen. Finally, both impaired function of mitochondria and hypoxia elevate fibrin protein level and amplify hemostasis as disseminated in- tracapillary coagulation (DIC). In any case, it is very interesting and remains to be answered whether imbalance in prooxidant-antioxidant homeostasis has causal relationship with transformation of SC to CSC.
Breast cancer is a leading cause of mortality and morbidity in women, mostly due to high metastatic capacity of mammary carcinoma cells. It has been revealed recently that metastases of breast cancer comprise a fraction of specific stem-like cells, denoted as cancer stem cells (CSCs). Breast CSCs, expressing specific surface markers CD44+CD24-/lowESA+ usually disseminate in the bone marrow, being able to spread further and cause late metastases. The fundamental factor influencing the growth of CSCs is the microenvironment, especially the interaction of CSCs with extracellular matrix (ECM). The structure and function of ECM proteins, such as the dominating ECM protein collagen, is influenced not only by cancer cells but also by various cancer treatments. Since surgery, radio and chemotherapy are associated with oxidative stress we analyzed the growth of breast cancer CD44+CD24-/lowESA+ cell line SUM159 cultured on collagen matrix in vitro, using either native collagen or the one modified by hydroxyl radical. While native collagen supported the growth of CSCs, oxidatively modified one was not supportive. The SUM159 cell cultures were further exposed to a supraphysiological (35 µM) dose of the major bioactive lipid peroxidation product 4-hydroxynonenal (HNE), a well known as "second messenger of free radicals", which has a strong affinity to bind to proteins and acts as a cytotoxic or as growth regulating signaling molecule. Native collagen, but not oxidised, abolished cytotoxicity of HNE, while oxidized collagen did not reduce cytotoxicity of HNE at all. These preliminary findings indicate that beside direct cytotoxic effects of anticancer therapies consequential oxidative stress and lipid peroxidation modify the microenvironment of CSCs influencing oxidative homeostasis that could additionally act against cancer.
Neoplastic cells which co-form tumors are usually subjected to various stress factors, mainly hypoxia and shortage of nutrient factors. Such cells employ different strategies that permit their survival under such conditions. Experiments in vitro are usually carried out in the presence of 21% oxygen and medium supplemented with 10% FBS. Altering these parameters can approximate the in vivo conditions found within tumor mass. The present paper reports certain properties (especially ability to metastasize) of B16-F10 cells able to grow upon exposure to altered growth conditions (medium supplemented with 0.06% FBS or presence of 1% oxygen for 24 or 72 hours). These properties were compared with those of control cells cultured in the presence of 21% oxygen and in medium supplemented with 10% FBS. Some properties of the cells exposed to medium supplemented with 0.06% FBS differ from those of cells cultured under low oxygenation conditions (ability to form metastases, to migrate, or to express various proteins). Only the partial deprivation of oxygen did increase both the number of migrating cells and the number of metastases formed. Serum deficiency enhanced only the cell ability to metastasize, but not to migrate. It appears that cultured B16-F10 cells employ different adaptation strategies under conditions of oxygen shortage and those of serum deficiency. Under oxygen deprivation, such cells most likely undergo an epithelial-mesenchymal transition, whereas serum deficiency ("starvation"), while increasing the tumorigenicity of B16-F10 cells, does not induce the epithelial-mesenchymal transition.
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