Metabolism within the tumor microenvironment and its implication on cancer progression: an ongoing therapeutic target

Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages and tumor-infiltrating T cells, surround tumor cells in the so-called tumor microenvironment. Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the tumor microenvironment and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that tumor microenvironment is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with combined therapies including anti-tumor agents with those targeting stromal cell metabolism, anti-angiogenic drugs and/or immunotherapy are being developed as promising therapeutics.Mª Carmen Ocaña is recipient of a predoctoral FPU grant from the Spanish Ministry of Education, Culture and Sport. Supported by grants BIO2014-56092-R (MINECO and FEDER), P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript

Scientific basis for responses to low-dose exposures

The DOE Low Dose Radiation Research Program focuses on biological mechanisms involved in response to low doses of both low and high-LET radiation (<0.1Gy). This research program represents a merging of new technologies with cutting edge biological techniques associated with genomics. This merger enables observation of radiationinduced cellular and molecular changes previously undetectable. These low-dose responses define mechanisms of interaction of radiation with living systems, and characterize the shape of dose-response. The research from this program suggests radiation paradigms regarding the involvement of radiation in the carcinogenic process. New biological phenomena observed at low doses include initial radiation-induced DNA damage and repair, changes in gene expression, adaptive responses and bystander effects. However, information from this cellular-molecular level cannot be directly extrapolated to risks in human populations. Links must be carefully developed between dose-response relationships at the cell and tissue levels and risk to human populations. The challenge and the ultimate goal of the Program is to determine if basic scientific data can be combined with more traditional epidemiological methods to improve the estimation of radiation risk from low level radiation exposures

Cancer Risk Assessment: Should New Science be Applied? Workgroup summary

OAK-B135 A symposium discussing the implications of certain phenomena observed in radiation biology for cancer risk assessment in general. In July of 2002 a workshop was convened that explored some of the intercellular phenomena that appear to condition responses to carcinogen exposure. Effects that result from communication between cells that appear to either increase the sphere of damage or to modify the sensitivity of cells to further damage were of particular interest. Much of the discussion focused on the effects of ionizing radiation that were transmitted from cells directly hit to cells not receiving direct exposure to radiation (bystander cells). In cell culture, increased rates of mutation, chromosomal aberration, apoptosis, genomic instability, and decreased clonogenic survival have all been observed in cells that have experienced no direct radiation. In addition, there is evidence that low doses of radiation or certain chemicals give rise to adaptive responses in which the treated cells develop resistance to the effects of high doses given in subsequent exposures. Data were presented at the workshop indicating that low dose exposure of animals to radiation and some chemicals frequently reduces the spontaneous rate of mutation in vitro and tumor responses in vivo. Finally, it was concluded that considerable improvement in understanding of how genetic variation may modify the impact of these phenomena is necessary before the risk implications can be fully appreciated. The workshop participants discussed the substantive challenge that these data present with respect to simple linear methodologies that are currently used in cancer risk assessment and attempted to identify broad strategies by which these phenomena may start to be used to refine cancer risk assessment methods in the future

The Role of Radiation Induced Injury on Lung Cancer

This manuscript evaluates the role of cell killing, tissue disorganization, and tissue damage on the induction of lung cancer following low dose rate radiation exposures from internally deposited radioactive materials. Beagle dogs were exposed by inhalation to 90Y, 91Y, 144Ce, or 90Sr in fused clay particles. Dogs lived out their life span with complete pathology conducted at the time of death. The radiation dose per cell turnover was characterized and related to the cause of death for each animal. Large doses per cell turnover resulted in acute death from lung damage with extensive cell killing, tissue disorganization, chronic inflammatory disease, fibrosis, and pneumonitis. Dogs with lower doses per cell turnover developed a very high frequency of lung cancer. As the dose per cell turnover was further decreased, no marked tissue damage and no significant change in either life span or lung cancer frequency was observed. Radiation induced tissue damage and chronic inflammatory disease results in high cancer frequencies in the lung. At doses where a high frequency of chromosome damage and mutations would be predicted to occur there was no decrease in life span or increase in lung cancer. Such research suggests that cell killing and tissue damage and the physiological responses to that damage are important mechanisms in radiation induced lung cancer

Risk of Low Dose/Low Dose Rate Ionizing Radiation to Humans Symposium at the EMS 2009 Annual Meeting - September 2006

The low dose symposium thoughtfully addressed controversy of risk from low dose radiation exposure, hormesis and radon therapy. The stem cell symposium cogently considered the role of DNA damage and repair in hematopoietic stem cells underlying aging and malignancy and provocatively presented evidence that stem cells may have distinct morphologies and replicative properties, as well as special roles in cancer initiation. In the epigenetics symposium, studies illustrated the long range interaction of epigenetic mechanisms, the roles of CTCF and BORIS in region/specific regulation of epigenetic processes, the impact of DNA damage on epigenetic processes as well as links between epigenetic mechanisms and early nutrition and bystander effects

Very Large Amounts of Radiation are Required to Produce Cancer

The public fear of radiation is in part driven by the Linear No Threshold Hypothesis (LNTH), or the concept that each and every ionization increases the risk for cancer. Even if this were true, it is important to recognize that the increased risk is very small at low doses and cannot be detected. This paper demonstrates the large number of assumptions and extrapolations needed when using the LNTH to estimate low-dose cancer risk. The manuscript provides information at every level of biological organization suggesting that many of these linear assumptions do not hold. While the initial damage may be produced linearly with dose, the processing of that damage is very non-linear. Finally, the paper provides the unique prospective on radiation-induced cancer, demonstrating that it takes large amounts (total energy) of radiation delivered to large populations to detect an increase in cancer frequency. These observations are supported by both theoretical calculations and examples based on past human radiation exposure