Normal stem cells in cancer prone epithelial tissues

The concept of a cancer stem cell is not a new one, being first suggested over 100 years ago. Over recent years the concept has enjoyed renewed enthusiasm, partly because of our growing understanding of the nature of somatic stem cells, but also because of a growing realisation that the development of strategies that target cancer stem cells may offer considerable advantages over conventional approaches. However, despite this renewed enthusiasm the existence of cancer stem cells remains controversial in many tumour types and any potential relationship to the normal stem cell pool remains poorly defined. This review summarises key elements of our understanding of the normal stem cell populations within animal models of the predominant cancer prone epithelial tissues, and further investigates the potential links between these populations and putative cancer stem cells

Genetic diversity and host alternation of the egg parasitoid Oencyrtus pityocampae between the pine processionary moth and caper bug

Research ArticleThe increased use of molecular tools for species identification in recent decades revealed that each of many apparently generalist parasitoids are actually a complex of morphologically similar congeners, most of which have a rather narrow host range. Ooencyrtus pityocampae (OP), an important egg parasitoid of the pine processionary moth (PPM), is considered a generalist parasitoid. OP emerges from PPM eggs after winter hibernation, mainly in spring and early summer, long before the eggs of the next PPM generation occurs. The occurrence of OP in eggs of the variegated caper bug (CB) Stenozygum coloratum in spring and summer suggests that OP populations alternate seasonally between PPM and CB. However, the identity of OP population on CB eggs seemed uncertain; unlike OP-PPM populations, the former displayed apparently high male/female ratios and lack of attraction to the PPM sex pheromone. We studied the molecular identities of the two populations since the morphological identification of the genus Ooencyrtus, and OP in particular, is difficult. Sequencing of COI and ITS2 DNA fragments and AFLP analysis of individuals from both hosts revealed no apparent differences between the OP-PPM and the OP-CB populations for both the Israeli and the Turkish OPs, which therefore supported the possibility of host alternation. Sequencing data extended our knowledge of the genetic structure of OP populations in the Mediterranean area, and revealed clear separation between East and West Mediterranean populations. The overall level of genetic diversity was rather small, with the Israeli population much less diverse than all others; possible explanations for this finding are discussed. The findings support the possibility of utilizing the CB and other hosts for enhancing biological control of the PPMinfo:eu-repo/semantics/publishedVersio

Emerging evidence of a link between the polycystins and the mTOR pathways

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by the formation of renal cysts. This disease can be caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC-1) and -2 (PC-2), respectively

Crypt stem cells as the cells-of-origin of intestinal cancer

Intestinal cancer is initiated by Wnt- pathway- activating mutations in genes such as adenomatous polyposis coli ( APC). As in most cancers, the cell of origin has remained elusive. In a previously established Lgr5 ( leucine- rich- repeat containing G- protein-coupled receptor 5) knockin mouse model, a tamoxifen- inducible Cre recombinase is expressed in long- lived intestinal stem cells(1). Here we show that deletion of Apc in these stem cells leads to their transformation within days. Transformed stem cells remain located at crypt bottoms, while fuelling a growing microadenoma. These microadenomas show unimpeded growth and develop into macroscopic adenomas within 3-5 weeks. The distribution of Lgr5(+) cells within stem- cell- derived adenomas indicates that a stem cell/ progenitor cell hierarchy is maintained in early neoplastic lesions. When Apc is deleted in short- lived transit- amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls. Even after 30 weeks, large adenomas are very rare in these mice. We conclude that stem- cell- specific loss of Apc results in progressively growing neoplasia

Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy.

Many tumour cells show dependence on exogenous serine and dietary serine and glycine starvation can inhibit the growth of these cancers and extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression of the de novo serine synthesis pathway (SSP) enzymes or activation of oncogenes that drive enhanced serine synthesis. Here we show that inhibition of PHGDH, the first step in the SSP, cooperates with serine and glycine depletion to inhibit one-carbon metabolism and cancer growth. In vitro, inhibition of PHGDH combined with serine starvation leads to a defect in global protein synthesis, which blocks the activation of an ATF-4 response and more broadly impacts the protective stress response to amino acid depletion. In vivo, the combination of diet and inhibitor shows therapeutic efficacy against tumours that are resistant to diet or drug alone, with evidence of reduced one-carbon availability. However, the defect in ATF4-response seen in vitro following complete depletion of available serine is not seen in mice, where dietary serine and glycine depletion and treatment with the PHGDH inhibitor lower but do not eliminate serine. Our results indicate that inhibition of PHGDH will augment the therapeutic efficacy of a serine depleted diet