[Abstract unavailable

Cancer stem cells (CSCs) have been identified in hematopoietic and solid tumors. However, their precursors—namely, precancerous stem cells (pCSCs) —have not been characterized. Here we experimentally define the pCSCs that have the potential for both benign and malignant differentiation, depending on environmental cues. While clonal pCSCs can develop into various types of tissue cells in immunocompetent mice without developing into cancer, they often develop, however, into leukemic or solid cancers composed of various types of cancer cells in immunodeficient mice. The progress of the pCSCs to cancers is associated with the up-regulation of c-kit and Sca-1, as well as with lineage markers. Mechanistically, the pCSCs are regulated by the PIWI/AGO family gene called piwil2. Our results provide clear evidence that a single clone of pCSCs has the potential for both benign and malignant differentiation, depending on the environmental cues. We anticipate pCSCs to be a novel target for the early detection, prevention, and therapy of cancers.

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pp72syk is essential for development and function of several hematopoietic cells, and it becomes activated through tandem SH2 interaction with ITAM motifs in immune response receptors. Since Syk is also activated through integrins, which do not contain ITAMs, a CHO cell model system was used to study Syk activation by the platelet integrin, alpha IIb beta 3. As in platelets, Syk underwent tyrosine phosphorylation and activation during CHO cell adhesion to alpha IIb beta 3 ligands, including fibrinogen. This involved Syk autophosphorylation and the tyrosine kinase activity of Src, and it exhibited two novel features. Firstly, unlike alpha IIb beta 3-mediated activation of pp125FAK, Syk activation could be triggered by the binding of soluble fibrinogen and abolished by truncation of the alpha IIb or beta 3 cytoplasmic tail, and it was resistant to inhibition by cytochalasin D. Secondly, it did not require phosphorylated ITAMs since it was unaffected by disruption of an ITAM-interaction motif in the SH2(C) domain of Syk or by simultaneous overexpression of the tandem SH2 domains. These studies demonstrate that Syk is a proximal component in alpha IIb beta 3 signaling and is regulated as a consequence of intimate functional relationships with the alpha IIb beta 3 cytoplasmic tails and with Src or a closely related kinase. Furthermore, there are fundamental differences in the activation of Syk by alpha IIb beta 3 and immune response receptors, suggesting a unique role for integrins in Syk function.

The gut microbiota plays an important role in maintaining intestinal homeostasis. Dysbiosis is associated with intestinal tumorigenesis. Deoxycholic acid (DCA), a secondary bile acid increased by a western diet, correlates with intestinal carcinogenesis. However, evidence relating bile acids, intestinal microbiota and tumorigenesis are limited. In our study, we investigated the effect of DCA on induction of intestinal dysbiosis and its roles in intestinal carcinogenesis. Alteration of the composition of the intestinal microbiota was induced in DCA-treated APC mice, which was accompanied by impaired intestinal barrier, gut low grade inflammation and tumor progression. The transfer of fecal microbiota from DCA-treated mice to another group of Apc mice increased tumor multiplicity, induced inflammation and recruited M2 phenotype tumor-associated macrophages. Importantly, the fecal microbiota transplantation activated the tumor-associated Wnt/β-catenin signaling pathway. Moreover, microbiota depletion by a cocktail of antibiotics was sufficient to block DCA-induced intestinal carcinogenesis, further suggesting the role of dysbiosis in tumor development. Our study demonstrated that alteration of the microbial community induced by DCA promoted intestinal carcinogenesis.

How a cancer is initiated and established remains elusive despite all the advances in decades of cancer research. Recently the cancer stem cell (CSC) hypothesis has been revived, challenging the long-standing model of ‘clonal evolution’ for cancer development and implicating the dawning of a potential cure for cancer [1]. The recent identification of pre-cancerous stem cells (pCSCs) in cancer, an early stage of CSC development, however, implicates that the clonal evolution is not contradictory to the CSC hypothesis but is rather an aspect of the process of CSC development [2]. The discovery of pCSC has revealed and will continue to reveal the volatile properties of CSC with respect to their phenotype, differentiation and tumourigenic capacity during initiation and progression. Both pCSC and CSC might also serve as precursors of tumour stromal components such as tumour vasculogenic stem/progenitor cells (TVPCs). Thus, the CSC hypothesis covers the developing process of tumour-initiating cells (TIC) → pCSC → CSC → cancer, a cellular process that should parallel the histological process of hyperplasia/metaplasia (TIC) → pre-cancerous lesions (pCSC) → malignant lesions (CSC → cancer). The embryonic stem (ES) cell and germ line stem (GS) cell genes are subverted in pCSCs. Especially the GS cell protein piwil2 may play an important role during the development of TIC → pCSC → CSC, and this protein may be used as a common biomarker for early detection, prevention, and treatment of cancer. As cancer stem cell research is yet in its infancy, definitive conclusions regarding the role of pCSC cannot be made at this time. However, this review will discuss what we have learned from pCSC and how this has led to innovative ideas that may eventually have major impacts on the understanding and treatment of cancer.

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BackgroundHypertrophic scars (HS) generally occur after injury to the deep layers of the dermis, resulting in functional deficiency for patients. Growing evidence has been identified that the supernatant of adipose tissue-derived stem cells (ADSCs) significantly ameliorates fibrosis of different tissues, but limited attention has been paid to its efficacy on attenuating skin fibrosis. In this study, we explored the effect and possible mechanism of ADSC-conditioned medium (ADSC-CM) on HS.MethodReal-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of collagen I (Col1), collagen III (Col3), and α-smooth muscle actin (α-SMA) after fibroblasts and cultured HS tissues were stimulated with ADSC-CM and p38 inhibitor/activator. Immunofluorescence staining was performed to test the expression of α-SMA. Masson’s trichrome staining, hematoxylin and eosin (H&E) staining, and immunohistochemistry staining were carried out to assess the histological and pathological change of collagen in the BALB/c mouse excisional model. All data were analyzed by using SPSS17.0 software. Statistical analysis was performed by Student’s t tests.ResultsThe in vitro and ex vivo study revealed ADSC-CM decreased the expression of Col1, Col3, and α-SMA. Together, thinner and orderly arranged collagen was manifested in HS tissues cultured with ADSC-CM. Dramatically, the assessed morphology showed an accelerated healing rate, less collagen deposition, and col1- and col3-positive cells in the ADSC-CM treated group. Importantly, the protein level of p-p38 was downregulated in a concentration-dependent manner in HS-derived fibroblasts with ADSC-CM treatment, which further decreased the expression of p-p38 after the application of its inhibitor, SB203580. SB203580 led to an obvious decline in the expression of Col1, Col3, and α-SMA in fibroblasts and cultured HS tissues and presented more ordered arrangement and thinner collagen fibers in BALB/c mice. Lastly, anisomycin, an agonist of p38, upregulated the expression of fibrotic proteins and revealed more disordered structure and denser collagen fibers.ConclusionThis study demonstrated that ADSC-CM could decrease collagen deposition and scar formation in in vitro, ex vivo and in vivo experiments. The regulation of the p38/MAPK signaling pathway played an important role in the process. The application of ADSC-CM may provide a novel therapeutic strategy for HS treatment, and the anti-scarring effect can be achieved by inhibition of the p38/MAPK signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0356-6) contains supplementary material, which is available to authorized users.