Modeling of Patient-Derived Xenografts in Colorectal Cancer

Abstract

Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell-line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient derived xenografts (PDXs) in colorectal cancer (CRC) are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target and drug discovery. Successful PDX engraftment is hypothesized to be related to a series of anecdotal variables namely, tissue source, cancer stage, tumor grade, acquisition strategy, time to implantation, exposure to prior systemic therapy, and genomic heterogeneity of tumors. Although these factors at large can influence practices and patterns related to xenotransplantation, their relative significance in determining the success of establishing PDXs is uncertain. Accordingly, we systematically examined the predictive ability of these factors in establishing PDXs using 90 CRC patient specimens that were subcutaneously implanted into immunodeficient mice. Fifty (56%) PDXs were successfully established. Multivariate analyses showed tissue acquisition strategy [surgery 72.0% (95% confidence interval (CI): 58.2–82.6) vs. biopsy 35% (95%CI: 22.1–50.6%)] to be the key determinant for successful PDX engraftment. These findings contrast with current empiricism in generating PDXs and can serve to simplify or liberalize PDX modelling protocols. Better understanding the relative impact of these factors on efficiency of PDX formation will allow for pervasive integration of these models in care of CRC patients.

CMScaller: an R package for consensus molecular subtyping of colorectal cancer pre-clinical models

“…Similarly, caution is warranted in highly selected datasets where molecular distributions are expected, or known, to severely deviate from pCRC cohorts, including metastatic samples 42 . Importantly, for both organoids and PDXs, it has been shown that the models recapitulate the heterogeneity of their original tumors 14 , 15 , 25 . However, to assess potential bias, we recommend analyzing CMS-associations of additional molecular markers, for instance MSI-status and BRAF mutations.…”

“…The original classifier was developed specifically for primary CRCs (pCRC), and it was recently shown that it fails to identify the CM S1 -immune and CM S4 -mesenchymal groups in cell lines, patient-derived organoids and xenografts (PDX) 15 , 18 – 20 , due to the absence of human immune-related signatures, stromal components and extra-cellular matrix in cell cultures and animal models 7 , 10 , 18 – 22 . However, at least some CRC cell lines are mesenchymal-like 5 , 16 , 23 , 24 and both organoids and PDXs can be established with minimal bias in terms of clinical and molecular covariates of the originating tumors 14 , 15 , 25 . This indicates that the apparent lack of CM S4 -like models is not a result of biological adaptation to or selection for culturing conditions.…”

Comprehensive comparison of patient-derived xenograft models in Hepatocellular Carcinoma and metastatic Liver Cancer

“…These results revealed that the engraftment rate of PDXs was different according to implanted tumor types. PDX models are currently established in variety of cancers, including colorectal 23 , pancreatic 24 , breast 25 , lung 26 , prostate 27 and ovarian cancer 28 . However, reports about PDX models of HCC were rare.…”

A new aggressive xenograft model of human colon cancer using cancer-associated fibroblasts

“…These samples are obtained fresh from tumor and should be implanted as soon as possible within the first 24 h (Rashidi et al, 2000;Fu et al, 1991). PDX has the advantage Full-size  DOI: 10.7717/peerj.9045/ fig-4 that the animal receives the full tumor repertoire from the patient: tumor and the peritumoral inflammatory reaction (Katsiampoura et al, 2017). Additionally, these would be appropriate to trial personalized treatments: the patient's tumor is transplanted in a series of animals that are treated with diverse drugs, and the one which best controls the tumor would be used in the patient (Okada, Vaeteewoottacharn & Kariya, 2018;Williams, 2018).…”

“…Additionally, these would be appropriate to trial personalized treatments: the patient's tumor is transplanted in a series of animals that are treated with diverse drugs, and the one which best controls the tumor would be used in the patient (Okada, Vaeteewoottacharn & Kariya, 2018;Williams, 2018). Nevertheless, this method has its limitations as well: it requires the use of animals that lack an immune system, the stroma that forms is murine and not human, and sometimes does not develop metastases (Katsiampoura et al, 2017). In addition, its clinical use is not without difficulties: with slow tumor growth, it has to be transferred to other animals to have a sufficient number for treatments, need for controls and costs involved.…”