Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy

Patients generally die of cancer after the failure of current therapies to eliminate residual disease. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. It has been proposed, therefore, that failure to effectively treat cancer may in part be due to preferential resistance of these CSC to chemotherapeutic agents. The subpopulation of human colorectal tumor cells with an ESA(+)CD44(+) phenotype are uniquely responsible for tumorigenesis and have the capacity to generate heterogeneous tumors in a xenograft setting (i.e. CoCSC). We hypothesized that if non-tumorigenic cells are more susceptible to chemotherapeutic agents, then residual tumors might be expected to contain a higher frequency of CoCSC.Xenogeneic tumors initiated with CoCSC were allowed to reach approximately 400 mm(3), at which point mice were randomized and chemotherapeutic regimens involving cyclophosphamide or Irinotecan were initiated. Data from individual tumor phenotypic analysis and serial transplants performed in limiting dilution show that residual tumors are enriched for cells with the CoCSC phenotype and have increased tumorigenic cell frequency. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Aldehyde dehydrogenase 1 gene expression and enzymatic activity are elevated in CoCSC and using an in vitro culture system that maintains CoCSC as demonstrated by serial transplants and lentiviral marking of single cell-derived clones, we further show that ALDH1 enzymatic activity is a major mediator of resistance to cyclophosphamide: a classical chemotherapeutic agent.CoCSC are enriched in colon tumors following chemotherapy and remain capable of rapidly regenerating tumors from which they originated. By focusing on the biology of CoCSC, major resistance mechanisms to specific chemotherapeutic agents can be attributed to specific genes, thereby suggesting avenues for improving cancer therapy

Effects of a predatory fish on a tropical detritus-based food web

In contrast to that for grazing systems, relatively little information exists for trophic cascades in detritus-based stream food webs, which are predominant in forested headwater streams. Predator–prey interactions are thought to be weak in these systems, but studies are very scarce, their results are equivocal, and they do not separate the effect of direct consumption from a behavioural response of shredders. We examined the effect of predatory fish on leaf litter breakdown in headwater tropical Australian streams at three levels: (1) the behavioural response of shredder species to predator presence as indicated by chemical cues; (2) the rates of leaf breakdown resulting from shredder activity; and (3) the relationship between shredder species richness and leaf breakdown rates. Our results suggest that predatory fish can have a trait-mediated effect on detritus-based food webs in streams, by reducing consumer activity. We identified reductions in short-term overall activity in response to the presence of predatory fish cues, comparable to those found for grazers. We also observed a visible, albeit statistically non-significant, reduction in consumption rates. Shredder species richness did not affect leaf breakdown rates, and fish presence did not modify this relationship or the differences in breakdown rates among species, suggesting that the overall reduction in leaf breakdown caused by fish presence is due to a reduction in activity in every species. Thus, our laboratory studies have shown that there can be a behavioural basis for trait-mediated trophic cascades linked to fish presence in detrital food webs in streams. However, the strength of fish effects depends on environmental circumstances, and field studies of litter breakdown in streams with and without predatory fish are required if we are to elucidate the ecological significance of our observations