Cancer cell adaptation to chemotherapy

BACKGROUND: Tumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Studies of human tumors show that cells adapt to chemotherapy, but it has been largely assumed that clonal selection leads to the resistance of recurrent tumors. METHODS: Cells derived from 47 tumors of breast, ovarian, esophageal, and colorectal origin and 16 paired esophageal biopsies were exposed to anticancer agents (cisplatin; 5-fluorouracil; epirubicin; doxorubicin; paclitaxel; irinotecan and topotecan) in short-term cell culture (6 days). Real-time quantitative PCR was used to measure up- or down-regulation of 16 different resistance/target genes, and when tissue was available, immunohistochemistry was used to assess the protein levels. RESULTS: In 8/16 paired esophageal biopsies, there was an increase in the expression of multi-drug resistance gene 1 (MDR1) following epirubicin + cisplatin + 5-fluorouracil (ECF) chemotherapy and this was accompanied by increased expression of the MDR-1 encoded protein, P-gp. Following exposure to doxorubicin in vitro, 13/14 breast carcinomas and 9/12 ovarian carcinomas showed >2-fold down-regulation of topoisomerase IIα (TOPOIIα). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIα in 6/7 colorectal tumors and 8/10 ovarian tumors. CONCLUSION: This study suggests that up-regulation of resistance genes or down-regulation in target genes may occur rapidly in human solid tumors, within days of the start of treatment, and that similar changes are present in pre- and post-chemotherapy biopsy material. The molecular processes used by each tumor appear to be linked to the drug used, but there is also heterogeneity between individual tumors, even those with the same histological type, in the pattern and magnitude of response to the same drugs. Adaptation to chemotherapy may explain why prediction of resistance mechanisms is difficult on the basis of tumor type alone or individual markers, and suggests that more complex predictive methods are required to improve the response rates to chemotherapy

Exploring the bioactive landscape of the gut microbiota to identify metabolites underpinning human health

The healthy human gut is colonised by a diverse microbial community (gut microbiota) that provides a variety of ecological and metabolic functions relevant to host health and well-being. Our early understanding and appreciation of the functional capacity of the microbiota was primarily informed by culture-dependent analyses. However, it is now known that the vast majority of gut microbes are resistant to cultivation and remain unrepresented by cultured isolates. Consequently, much of our current awareness of the true biological potential inherent to these communities has been provided by culture-independent (meta)genomic approaches which have revealed that the genetic potential of the gut microbiota is as much as 150 times greater than that of the human genome itself. Despite these advances it is now increasingly accepted that efforts to dissect the functionalities encoded in the human microbiome have not kept pace with DNA sequencing based technologies. For instance, the microbiome encodes a plethora of bioactive peptides and metabolites that affect host health, however, the function(s), mechanism(s) of action and the genetic and regulatory networks underpinning these bioactives remain largely cryptic. Here, we explore the NF-?B suppressive bioactive landscape of the gut microbiota-in particular, we provide an overview of our current understanding of the gut microbiota and propose the integration of new culture-dependent approaches with improved screening, metabolomic and genetic strategies offers new opportunities to identify novel bioactives, and elucidate the relationship between the gut microbiota associated metabolome and host health