Evidence of two types of balance between stem cell mitosis and enterocyte nucleus growth in the Drosophila midgut.

Systemic and stem cell niche-emanating cytokines and growth factors can promote regeneration, through mitosis. High mitosis, however, predisposes for all types of cancer and, thus, a trade-off exists between regeneration capacity and tissue homeostasis. Here, we study the role of tissue-intrinsic regenerative signaling in stem cell mitosis of adult Drosophila midgut of different genetic backgrounds. We provide evidence of two naturally occurring types of balance between mitosis and enterocyte nucleus growth: one based mostly on stem cell mitosis producing new cells and the other based mostly on the degree of young enterocyte nucleus size increase. Mitosis promotes intestinal host defense to infection, but predisposes for dysplasia in the form of stem cell-like clusters. Enterocyte nucleus growth also promotes host defense, without the drawback of promoting dysplasia. Through quantitative genetics, we identified eiger as an autocrine and paracrine inducer of stem cell mitosis. eiger expression in immature epithelial cells tilts the balance towards mitosis and dysplasia via a positive-feedback loop of highly mitotic stem cells sustaining more small nucleus enterocytes, which in turn supply more Eiger.

Regulation of Metastatic Tumor Dormancy and Emerging Opportunities for Therapeutic Intervention.

Cancer recurrence and metastasis, following successful treatment, constitutes a critical threat in clinical oncology and are the leading causes of death amongst cancer patients. This phenomenon is largely attributed to metastatic tumor dormancy, a rate-limiting stage during cancer progression, in which disseminated cancer cells remain in a viable, yet not proliferating state for a prolonged period. Dormant cancer cells are characterized by their entry into cell cycle arrest and survival in a quiescence state to adapt to their new microenvironment through the acquisition of mutations and epigenetic modifications, rendering them resistant to anti-cancer treatment and immune surveillance. Under favorable conditions, disseminated dormant tumor cells 're-awake', resume their proliferation and thus colonize distant sites. Due to their rarity, detection of dormant cells using current diagnostic tools is challenging and, thus, therapeutic targets are hard to be identified. Therefore, unraveling the underlying mechanisms required for keeping disseminating tumor cells dormant, along with signals that stimulate their "re-awakening" are crucial for the discovery of novel pharmacological treatments. In this review, we shed light into the main mechanisms that control dormancy induction and escape as well as emerging therapeutic strategies for the eradication of metastatic dormant cells, including dormancy maintenance, direct targeting of dormant cells and re-awakening dormant cells. Studies on the ability of the metastatic cancer cells to cease proliferation and survive in a quiescent state before re-initiating proliferation and colonization years after successful treatment, will pave the way toward developing innovative therapeutic strategies against dormancy-mediated metastatic outgrowth.

Remodelling of oxygen-transporting tracheoles drives intestinal regeneration and tumorigenesis in Drosophila.

The Drosophila trachea, as the functional equivalent of mammalian blood vessels, senses hypoxia and oxygenates the body. Here, we show that the adult intestinal tracheae are dynamic and respond to enteric infection, oxidative agents and tumours with increased terminal branching. Increased tracheation is necessary for efficient damage-induced intestinal stem cell (ISC)-mediated regeneration and is sufficient to drive ISC proliferation in undamaged intestines. Gut damage or tumours induce HIF-1α (Sima in Drosophila), which stimulates tracheole branching via the FGF (Branchless (Bnl))-FGFR (Breathless (Btl)) signalling cascade. Bnl-Btl signalling is required in the intestinal epithelium and the trachea for efficient damage-induced tracheal remodelling and ISC proliferation. Chemical or Pseudomonas-generated reactive oxygen species directly affect the trachea and are necessary for branching and intestinal regeneration. Similarly, tracheole branching and the resulting increase in oxygenation are essential for intestinal tumour growth. We have identified a mechanism of tracheal-intestinal tissue communication, whereby damage and tumours induce neo-tracheogenesis in Drosophila, a process reminiscent of cancer-induced neoangiogenesis in mammals.