Chronic inflammation is frequently associated with malignant growth and is thought to promote and enhance tumor progression, although the mechanisms which regulate this relationship remain elusive. We reported previously that interleukin (IL)-1B promoted tumor progression by enhancing the accumulation of myeloid-derived suppressor cells (MDSC), and hypothesized that inflammation leads to cancer through the production of MDSC which inhibit tumor immunity. If inflammation-induced MDSC promote tumor progression by blocking antitumor immunity, then a reduction in inflammation should reduce MDSC levels and delay tumor progression, whereas an increase in inflammation should increase MDSC levels and hasten tumor progression. We have tested this hypothesis using the 4T1 mammary carcinoma and IL-1 receptor (IL-1R)-deficient mice which have a reduced potential for inflammation, and IL-1R antagonist-deficient mice, which have an increased potential for inflammation. Consistent with our hypothesis, IL-1R-deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1B-induced expansion of MDSC. In contrast, excessive inflammation in IL-1R antagonistdeficient mice promotes the accumulation of MDSC and produces MDSC with enhanced suppressive activity. These results show that immune suppression by MDSC and tumor growth are regulated by the inflammatory milieu and support the hypothesis that the induction of suppressor cells which downregulate tumor immunity is one of the mechanisms linking inflammation and cancer.

Epidemiological and experimental observations support the hypothesis that chronic inflammation contributes to cancer development and progression; however, the mechanisms underlying the relationship between inflammation and cancer are poorly understood. To study these mechanisms, we have transfected the mouse 4T1 mammary carcinoma with the proinflammatory cytokine IL-1β to produce a chronic inflammatory microenvironment at the tumor site. Mice with 4T1/IL-1β tumors have a decreased survival time and elevated levels of immature splenic Gr1+CD11b+ myeloid-derived cells. These myeloid suppressor cells (MSC) are present in many patients with cancer and inhibit the activation of CD4+ and CD8+ T lymphocytes. 4T1/IL-1β-induced MSC do not express the IL-1R, suggesting that the cytokine does not directly activate MSC. Neither T or B cells nor NKT cells are involved in the IL-1β-induced increase of MSC because RAG2−/− mice and nude mice with 4T1/IL-1β tumors also have elevated MSC levels. MSC levels remain elevated in mice inoculated with 4T1/IL-1β even after the primary tumor is surgically removed, indicating that the IL-1β effect is long lived. Collectively, these findings suggest that inflammation promotes malignancy via proinflammatory cytokines, such as IL-1β, which enhance immune suppression through the induction of MSC, thereby counteracting immune surveillance and allowing the outgrowth and proliferation of malignant cells.

We investigate how changes in food availability during development affected the timing of and body size at metamorphosis in two closely related species of tree frogs that use different larval habitats. We raised tadpoles of Hyla gratiosa (a temporary—pond breeder) and Hyla cinerea (a permanent—pond breeder) at two different temperatures on either constant resources or a regime in which we altered food levels at one of three different times during development. For both species, larval period was affected only by early changes in food level; early increases shortened larval period, and decreases lengthened it. The timing of metamorphosis of Hyla gratiosa showed greater plasticity than that of Hyla cinerea, because of its greater overall response to any food—level change and not because of any difference between species in the duration of the sensitive period. The two species showed comparable levels of plasticity in body size at metamorphosis; increases in food level produced larger body sizes, and decreases produced smaller sizes. However, in contrast to the pattern seen in larval period, later changes in food level had the greatest effect on body size. These results force a reexamination of current ideas about the adaptive significance of plasticity in the timing of metamorphosis in response to food availability in larval anurans. We offer a model of dynamic allocation that accommodates the extant data on this issue.

Natural diversity in aging and other life history patterns is a hallmark of organismal variation. Related species, populations, and individuals within populations show genetically based variation in life span and other aspects of age-related performance. Population differences are especially informative because these differences can be large relative to within-population variation and because they occur in organisms with otherwise similar genomes. We used experimental evolution to produce populations divergent for life span and late-age fertility and then used deep genome sequencing to detect sequence variants with nucleotide-level resolution. Several genes and genome regions showed strong signatures of selection, and the same regions were implicated in independent comparisons, suggesting that the same alleles were selected in replicate lines. Genes related to oogenesis, immunity, and protein degradation were implicated as important modifiers of late-life performance. Expression profiling and functional annotation narrowed the list of strong candidate genes to 38, most of which are novel candidates for regulating aging. Life span and early-age fecundity were negatively correlated among populations; therefore the alleles we identified also are candidate regulators of a major life-history trade-off. More generally, we argue that hitchhiking mapping can be a powerful tool for uncovering the molecular bases of quantitative genetic variation.

Summary 0[ We examined the numerical dynamics in four natural populations of the least killi_sh ðHeterandria formosa Agassiz "0744#Ł^to ascertain how those dynamics a}ec! ted the expression of key life!history traits and\ in turn\ whether life!history variation among populations might be responsible for di}erent dynamic properties[ Populations were chosen from two types of communities\ spring!fed rivers and lakes\ to examine the relative in~uence of community characteristics on these relationships[ 1[ Populations in lakes had lower densities\ more female!biased sex ratios and a smaller proportion of immature individuals than populations in rivers[ Predator faunas di}ered between habitats and the ratio of predator to H[ formosa density was higher in lakes than in rivers[ 2[ Females in lake populations were 24−39) larger than river females[ Female size was positively correlated with the number of broods carried by a female at any given time and the number of o}spring in a particular brood[ These correlations and the larger body size of females in lake populations indicate that the reproductive output per female was higher in lake than river populations[ 3[ Female size was negatively correlated with population density in two of the four populations[ After adjusting for the variation in female size\ brood size and brood numbers were negatively correlated with population density in only the highest density population[ 4[ Average o}spring size was negatively correlated with brood size in all of the populations\ indicating a general trade!o} between o}spring size and number[ The average o}spring size in the highest density population was as much as 34) larger than that of all other populations\ an e}ect independent of any phenotypic plasticity in o}spring size with respect to female body size or density[ 5[ The e}ects of density on female body size are the major avenue for negative feedback of population density on the subsequent dynamics through life!history expression[ Whether such an e}ect is stabilizing or destabilizing cannot yet be deter! mined[ If the variation in o}spring size among populations is adaptive\ it may be a prominent example of density!dependent life!history evolution[ Key!words] body size\ community composition\ demography\ density dependence\ life!history variation\ poeciliid _sh\ population dynamics[ Journal of Animal Ecology "0888# 57\ 484Ð505