The skin interfollicular epidermis (IFE) is the first barrier against the external environment and its maintenance is critical for survival. Two seemingly opposite theories have been proposed to ...explain IFE homeostasis. One posits that IFE is maintained by long-lived slow-cycling stem cells that give rise to transit-amplifying cell progeny, whereas the other suggests that homeostasis is achieved by a single committed progenitor population that balances stochastic fate. Here we probe the cellular heterogeneity within the IFE using two different inducible Cre recombinase–oestrogen receptor constructs targeting IFE progenitors in mice. Quantitative analysis of clonal fate data and proliferation dynamics demonstrate the existence of two distinct proliferative cell compartments arranged in a hierarchy involving slow-cycling stem cells and committed progenitor cells. After wounding, only stem cells contribute substantially to the repair and long-term regeneration of the tissue, whereas committed progenitor cells make a limited contribution.
Recent studies have shown that tissue-specific stem cells (SCs) found throughout the body respond differentially to DNA damage. In this review, we will discuss how different SC populations sense and ...functionally respond to DNA damage, identify various common and distinct mechanisms utilized by tissue-specific SCs to address DNA damage, and describe how these mechanisms can impact SC genomic integrity by potentially promoting aging, tissue atrophy, and/or cancer development. Finally, we will discuss how similar mechanisms operate in cancer stem cells (CSCs) and can mediate resistance to chemo- and radiotherapy.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In cancer, the epithelial-to-mesenchymal transition (EMT) is associated with tumour stemness, metastasis and resistance to therapy. It has recently been proposed that, rather than being a binary ...process, EMT occurs through distinct intermediate states. However, there is no direct in vivo evidence for this idea. Here we screen a large panel of cell surface markers in skin and mammary primary tumours, and identify the existence of multiple tumour subpopulations associated with different EMT stages: from epithelial to completely mesenchymal states, passing through intermediate hybrid states. Although all EMT subpopulations presented similar tumour-propagating cell capacity, they displayed differences in cellular plasticity, invasiveness and metastatic potential. Their transcriptional and epigenetic landscapes identify the underlying gene regulatory networks, transcription factors and signalling pathways that control these different EMT transition states. Finally, these tumour subpopulations are localized in different niches that differentially regulate EMT transition states.
Full text
Available for:
KISLJ, NUK, SBMB, UL, UM, UPUK
Squamous cell carcinoma (SCC) is the second most frequent skin cancer. The cellular origin of SCC remains controversial. Here, we used mouse genetics to determine the epidermal cell lineages at the ...origin of SCC. Using mice conditionally expressing a constitutively active KRas mutant (G12D) and an inducible CRE recombinase in different epidermal lineages, we activated Ras signaling in different cellular compartments of the skin epidermis and determined from which epidermal compartments Ras activation induces squamous tumor formation. Expression of mutant KRas in hair follicle bulge stem cells (SCs) and their immediate progeny (hair germ and outer root sheath), but not in their transient amplifying matrix cells, led to benign squamous skin tumor (papilloma). Expression of KRasG12D in interfollicular epidermis also led to papilloma formation, demonstrating that squamous tumor initiation is not restricted to the hair follicle lineages. Whereas no malignant tumor was observed after KRasG12D expression alone, expression of KRasG12D combined with the loss of p53 induced invasive SCC. Our studies demonstrate that different epidermal lineages including bulge SC are competent to initiate papilloma formation and that multiple genetic hits in the context of oncogenic KRas are required for the development of invasive SCC.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
For most types of cancers, the cell at the origin of tumour initiation is still unknown. Here, we used mouse genetics to identify cells at the origin of basal cell carcinoma (BCC), which is one of ...the most frequently occurring types of cancer in humans, and can result from the activation of the Hedgehog signalling pathway. Using mice conditionally expressing constitutively active Smoothened mutant (SmoM2), we activated Hedgehog signalling in different cellular compartments of the skin epidermis and determined in which compartments Hedgehog activation induces BCC formation. Activation of SmoM2 in hair follicle bulge stem cells and their transient amplifying progenies did not induce cancer formation, demonstrating that BCC does not originate from bulge stem cells, as previously thought. Using clonal analysis, we found that BCC arises from long-term resident progenitor cells of the interfollicular epidermis and the upper infundibulum. Our studies uncover the cells at the origin of BCC in mice and demonstrate that expression of differentiation markers in tumour cells is not necessarily predictive of the cancer initiating cells.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Mesenchymal stem cells (MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for regenerative medicine. They possess unique immunomodulatory properties, being capable of ...suppressing T‐cell responses and modifying dendritic cell differentiation, maturation, and function, whereas they are not inherently immunogenic, failing to induce alloreactivity to T cells and freshly isolated natural killer (NK) cells. To clarify the generation of host immune responses to implanted MSCs in tissue engineering and their potential use as immunosuppressive elements, the effect of MSCs on NK cells was investigated. We demonstrate that at low NK‐to‐MSC ratios, MSCs alter the phenotype of NK cells and suppress proliferation, cytokine secretion, and cyto‐toxicity against HLA‐class I– expressing targets. Some of these effects require cell‐to‐cell contact, whereas others are mediated by soluble factors, including transforming growth factor–β1 and prostaglandin E2, suggesting the existence of diverse mechanisms for MSC‐mediated NK‐cell suppression. On the other hand, MSCs are susceptible to lysis by activated NK cells. Overall, these data improve our knowledge of interactions between MSCs and NK cells and consequently of their effect on innate immune responses and their contribution to the regulation of adaptive immunity, graft rejection, and cancer immunotherapy.
The resistance of cancer cells to therapy is responsible for the death of most patients with cancer
. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in ...different cancer cells
. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ-a small GTPase that is preferentially expressed in EMT cancer cells-controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy.
Mesenchymal stem cells (MSCs) are multipotent cells defined by multilineage potential, ease to gene modification, and immunosuppressive ability, thus holding promise for tissue engineering, gene ...therapy, and immunotherapy. They exhibit a unique in vitro expansion capacity, which, however, does not compensate for the very low percentage in their niches given the vast numbers of cells required for the relative studies. Taking into consideration the lack of a uniform approach for MSC isolation and expansion, we attempted in this study, by comparing various culture conditions, to identify the optimal protocol for the large‐scale production of MSCs while maintaining their multilineage and immunosuppressive capacities. Our data indicate that, apart from the quality of fetal calf serum, other culture parameters, including basal medium, glucose concentration, stable glutamine, bone marrow mononuclear cell plating density, MSC passaging density, and plastic surface quality, affect the final outcome. Furthermore, the use of basic fi‐broblast growth factor (bFGF), the most common growth supplement in MSC culture media, greatly increases the proliferation rate but also upregulates HLA‐class I and induces low HLA‐DR expression. However, not only does this upregulation not elicit significant in vitro allogeneic T cell responses, but also bFGF‐cultured MSCs exhibit enhanced in vivo immunosuppressive potential. Besides, addition of bFGF affects MSC multilineage differentiation capacity, favoring differentiation toward the osteogenic lineage and limiting neurogenic potential. In conclusion, in this report we define the optimal culture conditions for the successful isolation and expansion of human MSCs in high numbers for subsequent cellular therapeutic approaches.
Adult stem cells (SCs) are at high risk of accumulating deleterious mutations because they reside and self-renew in adult tissues for extended periods. Little is known about how adult SCs sense and ...respond to DNA damage within their natural niche. Here, using mouse epidermis as a model, we define the functional consequences and the molecular mechanisms by which adult SCs respond to DNA damage. We show that multipotent hair-follicle-bulge SCs have two important mechanisms for increasing their resistance to DNA-damage-induced cell death: higher expression of the anti-apoptotic gene Bcl-2 and transient stabilization of p53 after DNA damage in bulge SCs. The attenuated p53 activation is the consequence of a faster DNA repair activity, mediated by a higher non-homologous end joining (NHEJ) activity, induced by the key protein DNA-PK. Because NHEJ is an error-prone mechanism, this novel characteristic of adult SCs may have important implications in cancer development and ageing.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•The CSC concept provided a means to develop novel more effective anti-cancer strategies.•Human cancers comprised heterogeneous populations of cells including CSCs.•CSCs have been shown to be ...involved in drug resistance.•There is a spatiotemporal variability in the CSC content of a given tumor.•Novel therapeutic strategies and novel small compounds are required to specifically target different types of CSCs.
Cancer stem cells (CSCs) are a subpopulation of cancer cells with high clonogenic capacity and ability to reform parental tumors upon transplantation. Resistance to therapy has been shown for several types of CSC and, therefore, they have been proposed as the cause of tumor relapse. Consequently, much effort has been made to design molecules that can target CSCs specifically and sensitize them to therapy. In this review, we summarize the mechanisms underlying CSC resistance, the potential biological targets to overcome resistance and the chemical compounds showing activity against different types of CSC. The chemical compounds discussed here have been divided according to their origin: natural, natural-derived and synthetic compounds.
Reviewing the small molecules that showed efficacy against CSCs is of crucial importance to stimulate the design of new promising anticancer compounds.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
