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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Immunology --- tumor microenvironment --- monocyte --- macrophage --- neutrophil --- immunosuppression --- immunotherapy --- tumor microenvironment --- monocyte --- macrophage --- neutrophil --- immunosuppression --- immunotherapy

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Gastrointestinal system --- Cancer. --- Gastrointestinal Neoplasms --- Immunotherapy. --- Tumor Microenvironment. --- immunology.

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The biological outcome of Hyaluronan (also hyaluronic acid, abbreviated HA) interaction with its CD44 or RHAMM receptors recently attracted much attention within the scientific community owing to a Nature article by Tian X et al. (Nature 2013; 499:346-9). The article described a life span exceeding 30 years in naked mole rats, whereas the maximal lifespan of mice, to which the naked mole rat is related, is only 4 years. This observation is accompanied by the finding that the naked mole rat, in contrast to the mouse, does not develop spontaneous tumors during this exceptional longevity. The article provides evidence that interaction of long tissue HA (6000-12,000 kDa) of the naked mole rat with cell surface CD44, in contrast to the interaction of short tissue HA (less than 3000 kDa) with the mouse CD44, makes the difference. More specifically, this communication shows that the interaction of short HA with fibroblasts’ CD44 imposes on them susceptibility for malignant transformation, whereas the corresponding interaction with long HA imposes on the fibroblasts a resistance to malignant transformation. The article does not explain the mechanism that underlines these findings. However, the articles, that will be published in the proposed Research Topic in the Inflammation section of Frontiers in Immunology, can bridge not only this gap, but also may explain why interaction between short HA and cell surface CD44 (or RHAMM, an additional HA receptor) enhances the development of inflammatory and malignant diseases. Furthermore, the articles included in the proposed Frontiers Research Topic will show that cancer cells and inflammatory cells share several properties related to the interaction between short HA and cell surface CD44 and/or RHAMM. These shared properties include: 1. Support of cell migration, which allows tumor metastasis and accumulation of inflammatory cells at the inflammation site; 2. Delivery of intracellular signaling, which leads to cell survival of either cancer cells or inflammatory cells; 3. Delivery of intracellular signaling, which activates cell replication and population expansion of either cancer cells or inflammatory cells; and 4. Binding of growth factors to cell surface CD44 of cancer cells or inflammatory cells (i.e., the growth factors) and their presentation to cells with cognate receptors (endothelial cells, fibroblasts), leading to pro-malignant or pro-inflammatory activities. Going back to the naked mole rat story, we may conclude from the proposed articles of this Frontiers Research Topic that the long HA, which displays anti-malignant effect, interferes with the above described pro-malignant potential of the short HA (perhaps by competing on the same CD44 receptor). Extrapolating this concept to Inflammation, the same mechanism (competition?) may be valid for inflammatory (and autoimmune) activities. If this is the case, long HA may be used for therapy of both malignant and inflammatory diseases. Moreover, targeting the interaction between short HA and CD44 (e.g. by anti-CD44 blocking antibodies) may display also a therapeutic effect on both malignant and inflammatory diseases, an issue that encourages not only fruitful exchange of views, but also practical experimental collaboration.

Autoimmunity --- hyaluronan --- therapy --- hyaluronan synthase --- Inflammation --- Tissue microenvironment --- CD44 --- Cancer --- Autoimmunity --- hyaluronan --- therapy --- hyaluronan synthase --- Inflammation --- Tissue microenvironment --- CD44 --- Cancer

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Science: general issues --- Biology, life sciences --- microenvironment --- extracellular matrix --- disease --- cancer --- aging --- microenvironment --- extracellular matrix --- disease --- cancer --- aging

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Plasticity is the hallmark of stem cells. At the same time, stem cells, like any other cell type, are influenced by their microenvironment and respond to it accordingly. A specific microenvironment is defined by a variety of factors, including biological and chemical factors, cell-cell interactions, but also metabolic and mechanical cues. Such dynamic and specialized microenvironment where the stem cells reside is considered a stem cell niche. Tissue injury as well as malignant tissue alterations lead to changes in the niche influencing the plasticity and biology of residing stem cells. Similarly, the niche changes upon tissue damage, which eventually induces differentiation of stem cells and ultimately regeneration of the tissue.

microenvironment --- stem cells --- tissue regeneration --- immunomodulation --- extracellular vesicles (EVs) --- oxygen tension --- plasticity --- imaging --- microenvironment --- stem cells --- tissue regeneration --- immunomodulation --- extracellular vesicles (EVs) --- oxygen tension --- plasticity --- imaging