The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.

Modulation of oxidative stress as an anticancer strategy.

The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers.

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TGFβ signalling in context.

Stem cells are defined as cells able to both extensively self-renew and differentiate into progenitors. Research data show that more resistant stem cells than common cancer cells exist in cancer patients.To identify unrecognized differences between cancer stem cells and cancer cells might be able to develope effective classification,diagnose and treat ment for cancer.

Stem Cells,Cancer and Cancer Stem Cells

Cadherin cell-adhesion proteins mediate many facets of tissue morphogenesis. The dynamic regulation of cadherins in response to various extracellular signals controls cell sorting, cell rearrangements and cell movements. Cadherins are regulated at the cell surface by an inside-out signalling mechanism that is analogous to the integrins in platelets and leukocytes. Signal-transduction pathways impinge on the catenins (cytoplasmic cadherin-associated proteins), which transduce changes across the membrane to alter the state of the cadherin adhesive bond.

Regulation of cadherin-mediated adhesion in morphogenesis

The intestinal epithelium is a single-cell layer that constitutes the largest and most important barrier against the external environment. It acts as a selectively permeable barrier, permitting the absorption of nutrients, electrolytes, and water while maintaining an effective defense against intraluminal toxins, antigens, and enteric flora. The epithelium maintains its selective barrier function through the formation of complex protein-protein networks that mechanically link adjacent cells and seal the intercellular space. The protein networks connecting epithelial cells form 3 adhesive complexes: desmosomes, adherens junctions, and tight junctions. These complexes consist of transmembrane proteins that interact extracellularly with adjacent cells and intracellularly with adaptor proteins that link to the cytoskeleton. Over the past decade, there has been increasing recognition of an association between disrupted intestinal barrier function and the development of autoimmune and inflammatory diseases. In this review we summarize the evolving understanding of the molecular composition and regulation of intestinal barrier function. We discuss the interactions between innate and adaptive immunity and intestinal epithelial barrier function, as well as the effect of exogenous factors on intestinal barrier function. Finally, we summarize clinical and experimental evidence demonstrating intestinal epithelial barrier dysfunction as a major factor contributing to the predisposition to inflammatory diseases, including food allergy, inflammatory bowel diseases, and celiac disease.

Intestinal barrier function: molecular regulation and disease pathogenesis.

Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a(+/+) and Foxo3a(-/-) mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-beta inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-beta inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-beta-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.

TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

Regulation of the Assembly and Adhesion Activity of E-cadherin by Nectin and Afadin for the Formation of Adherens Junctions in Madin-Darby Canine Kidney Cells

Involvement of LMO7 in the Association of Two Cell-Cell Adhesion Molecules, Nectin and E-cadherin, through Afadin and α-Actinin in Epithelial Cells

Although dysregulation of mTOR complex 1 (mTORC1) promotes leukemogenesis, how mTORC1 affects established leukemia is unclear. We investigated the role of mTORC1 in mouse hematopoiesis using a mouse model of conditional deletion of Raptor, an essential component of mTORC1. Raptor deficiency impaired granulocyte and B cell development but did not alter survival or proliferation of hematopoietic progenitor cells. In a mouse model of acute myeloid leukemia (AML), Raptor deficiency significantly suppressed leukemia progression by causing apoptosis of differentiated, but not undifferentiated, leukemia cells. mTORC1 did not control cell cycle or cell growth in undifferentiated AML cells in vivo. Transplantation of Raptor-deficient undifferentiated AML cells in a limiting dilution revealed that mTORC1 is essential for leukemia initiation. Strikingly, a subset of AML cells with undifferentiated phenotypes survived long-term in the absence of mTORC1 activity. We further demonstrated that the reactivation of mTORC1 in those cells restored their leukemia-initiating capacity. Thus, AML cells lacking mTORC1 activity can self-renew as AML stem cells. Our findings provide mechanistic insight into how residual tumor cells circumvent anticancer therapies and drive tumor recurrence.

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mTORC1 is essential for leukemia propagation but not stem cell self-renewal

Par-3 is a cell-polarity protein that regulates the formation of tight junctions (TJs) in epithelial cells, where claudin is a major cell-cell adhesion molecule (CAM). TJs are formed at the apical side of adherens junctions (AJs), where E-cadherin and nectin are major CAMs. We have revealed that nectin first forms cell-cell adhesions, and then recruits cadherin to nectin-based cell-cell adhesion sites to form AJs and subsequently recruits claudin to the apical side of AJs to form TJs. The cytoplasmic tail of nectin binds afadin and Par-3. Afadin regulates the formation of AJs and TJs cooperatively with nectin. Here, we studied the role of Par-3 in the formation of these junctions by using Par-3-knockdown MDCK cells. Par-3 was necessary for the formation of AJs and TJs but was not necessary for nectin-based cell-cell adhesion. Par-3 promoted the association of afadin with nectin, whereas afadin was not necessary for the association of Par-3 with nectin. However, the association of afadin with nectin alone was not sufficient for the formation of AJs or TJs, and Par-3 and afadin cooperatively regulated it. We describe here these novel roles of Par-3 in the formation of junctional complexes.

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Takako Ooshio

Papers

TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

Regulation of the Assembly and Adhesion Activity of E-cadherin by Nectin and Afadin for the Formation of Adherens Junctions in Madin-Darby Canine Kidney Cells

Involvement of LMO7 in the Association of Two Cell-Cell Adhesion Molecules, Nectin and E-cadherin, through Afadin and α-Actinin in Epithelial Cells

mTORC1 is essential for leukemia propagation but not stem cell self-renewal

Cooperative roles of Par-3 and afadin in the formation of adherens and tight junctions.