In vitro research
Together with surgery and radiotherapy, chemotherapy is one of the main cancer treatment modalities. Since its introduction, considerable efforts have been made by clinicians and researchers to optimize drug efficacy and minimize side-effects for the patients. Furthermore, the pharmaceutical industry has increased investments into drug discovery programs to provide new molecules and biologic agents for clinical development and the pharmaceutical market. However, the amount of cancer drugs removed from early clinical trials has reached a disturbing low, suggesting that preclinical development has not been successful in identifying agents that can modify the outcome of human cancer.
A standard in vitro screening of product libraries for novel anticancer agents mainly relies on cytotoxicity assays using established cancer cell lines grown as two-dimensional (2D) cultures that exhibit a rapid, uncontrolled growth phenotype. While this approach has several strengths, 2D cell cultures show important limitations as they are not capable of mimicking the complexity and heterogeneity of clinical tumors with a specific organization and architecture. Consequently, numerous signals that govern different cellular processes are lost when cells are grown in a 2D environment.
Three-dimensional (3D) growth of cancer cells is regarded as a more stringent and representative model on which to perform in vitro drug screening. For example, 3D cell cultures demonstrate cell-cell interaction, hypoxia, and differences in drug penetration. It is now commonly accepted that in vitro 3D cultures will be able to fill the gap between conventional 2D in vitro testing and animal models. To date, several types of 3D culture models have been developed. Tumor spheroids, 3D spheroidal architectures, are one of the most common and versatile scaffold-free methods for 3D cell culture. Starting from a single cell suspension, spheroids are formed either via self-assembly or forced growth as clusters.
In our lab we are currently optimizing two methods to produce in vitro tumor spheroids with the use of the random positioning machine (RPM) or using the hanging drop method. With the RPM, cells are exposed to simulated microgravity allowing them to clump together via self-assembly. The hanging drop method makes use of inverted droplets, forcing the cancer cells to grow in clusters.
In vivo research
Colorectal cancer (CRC) is the second most common identified malignancy worldwide and thus represents an important health and socioeconomical burden. Recent data based on metagenomics and experimental models suggest a strong contribution of the gut microbiome in modulating CRC development. Various studies have systemically showed a significant shift in microbial composition comparing the gut microbiome of CRC patients with healthy individuals, a phenomenon commonly referred to as dysbiosis. Particularly, the presence of certain types of bacterial populations such as Bacteroides fragilis, Escherichia coli, and Fusobacterium nucleatum have been associated with an increased risk for the development of CRC, while other bacteria including Lachnospiraceae species seem to have an antitumor effect in the colon by producing metabolites such as short-chain fatty acid butyrate promoting apoptosis of colonic cancer cells.
Radiotherapy plays an adjuvant role in the treatment of CRC. However, the usage of radiotherapy has been shown to cause mucositis and radiation-induced ulceration which drive substantial changes in the gut microbiome leading to intestinal dysbiosis in CRC patients. This radiation‐induced toxicity and its association with microbial dynamics, forms a medical problem that urgently needs addressing in order to have an effective intervention.