Establishment of patient derived colorectal tumor xenografts with diet induced treatment
Colorectal cancer (CRC) is one of the most common cancers among men and women, representing 10 % of the global cancer incidence according to the World Cancer Report (2014). Despite progress in early diagnosis and treatment (surgery, chemotherapy and radiotherapy), CRC are still high in mortality rate, causing almost 800000 deaths in 2015. Lifestyle and diet are considered major risk factors (1). Increased physical activity and a diet rich in fruit, vegetables, fish and white meat have shown to decrease the risk (2). Polyunsaturated fatty acids (PUFAs) as omega-3 have been reported to inhibit growth of cancer cells both in vitro and in vivo thus reported to have multiple anti-cancer effects.
Developing animal models is an utterly important tool to investigate treatment regimens and increase the knowledge about tumor biology in humans and animals, preclinical tools for the discovery of biomarkers, therapeutic targets and drugs and diagnosis of cancer. Patient derived xenograft (PDX) as animal models of CRC patients has been shown to be representative of the genetic and phenotypic variations from the original tumor correlating well with clinical responses to chemotherapy (3). Previously, our research group has developed human xenograft model by injecting colorectal cancer cells subcutaneously (s.c.) into the side flank of mouse models and further treating the tumor-bearing mice with an omega-3 rich diet (4). This year, a research manuscript demonstrated implantation of tumor xenografts s.c. into side flank of a PDX mouse model (5). The purpose on our study is to establish a similar model here at NTNU in collaboration with surgeons at St. Olavs Hospital in Trondheim by implanting patient derived tumor tissue s.c. into side flank of immunocompromised CIEA NOG mice (pilot: n=10+20; main: n=60). Tumor specimens (~50mm3) will be collected by surgery and placed in complete growth media during ischemic period prior to engraftment. The tumor will develop underneath the skin of the mice, and will be measured by a palpate tool up to human end point (HEP) of ~1500mm3. When this model is successfully established, we will continue the studies with diet induced treatment comprising increased percentage of the omega-3 fatty acids and further combination treatment with current chemotherapy for colorectal patients in addition to an autophagy mediator. The hypotheses involve reduced tumor growth of the treatment group receiving omega-3 rich diet in comparison to the control group. The study allows us to investigate the variation of sensitivity to omega-3 fatty acids of the different CRC patients which reach towards the research field of personalized medicine.
The use of patient material has been approved by the Regional Committee for Medical and Health Research Ethics (REC) including patients that have already planned lifesaving surgery and voluntarily agreed to contribute to this experiment by an informed consent.
Cell line derived xenografts (CDXs) will also be establish to compare the effect of the omega-3 supplemented and placebo nutrition drink on colorectal cancer cell lines with know degree of sensitivity towards omega-3 fatty acids.
Developing animal models is an utterly important tool to investigate treatment regimens and increase the knowledge about tumor biology in humans and animals, preclinical tools for the discovery of biomarkers, therapeutic targets and drugs and diagnosis of cancer. Patient derived xenograft (PDX) as animal models of CRC patients has been shown to be representative of the genetic and phenotypic variations from the original tumor correlating well with clinical responses to chemotherapy (3). Previously, our research group has developed human xenograft model by injecting colorectal cancer cells subcutaneously (s.c.) into the side flank of mouse models and further treating the tumor-bearing mice with an omega-3 rich diet (4). This year, a research manuscript demonstrated implantation of tumor xenografts s.c. into side flank of a PDX mouse model (5). The purpose on our study is to establish a similar model here at NTNU in collaboration with surgeons at St. Olavs Hospital in Trondheim by implanting patient derived tumor tissue s.c. into side flank of immunocompromised CIEA NOG mice (pilot: n=10+20; main: n=60). Tumor specimens (~50mm3) will be collected by surgery and placed in complete growth media during ischemic period prior to engraftment. The tumor will develop underneath the skin of the mice, and will be measured by a palpate tool up to human end point (HEP) of ~1500mm3. When this model is successfully established, we will continue the studies with diet induced treatment comprising increased percentage of the omega-3 fatty acids and further combination treatment with current chemotherapy for colorectal patients in addition to an autophagy mediator. The hypotheses involve reduced tumor growth of the treatment group receiving omega-3 rich diet in comparison to the control group. The study allows us to investigate the variation of sensitivity to omega-3 fatty acids of the different CRC patients which reach towards the research field of personalized medicine.
The use of patient material has been approved by the Regional Committee for Medical and Health Research Ethics (REC) including patients that have already planned lifesaving surgery and voluntarily agreed to contribute to this experiment by an informed consent.
Cell line derived xenografts (CDXs) will also be establish to compare the effect of the omega-3 supplemented and placebo nutrition drink on colorectal cancer cell lines with know degree of sensitivity towards omega-3 fatty acids.