Xenograft Studies

Contract Research Preclinical Oncology Services
Unique immunodeficient, syngenic, and humanized mouse and rat models

Xenograft Services

Unique immunodeficient, syngeneic, and humanized mouse and rat models.

Contact us to learn more about our comprehensive services for oncology research.

xenograft models

Find the Right Xenograft Model

Hera provides in vitro and in vivo oncology studies to leaders in industry and academia.  We have optimized a wide variety of xenograft, PDX, and syngeneic tumor models in both mice and our unique SRG rat OncoRat.

Request more information about our capabilities and expansive xenograft portfolio.

Identifying the right preclinical efficacy model involves a lot of choices: subcutaneous or orthotopic, mouse or rat xenograft host, cell line xenografts or patient-derived xenografts (PDX), and humanized immune system vs syngeneic.  Let our team of expert scientists advise on the selecting the perfect preclinical drug efficacy testing strategy.

Hera BioLabs - Press - Hera BioLabs Announces Exclusive Global License with Charles River

The SRG Rat: Building a Better Trap for Cancer

The SRG rat is an ideal host for human xenografts. It is a highly immunodeficient (SCID) rat on the Sprague-Dawley background similar to NSG mice, demonstrating enhanced immunodeficiency, lacking B-cells, T-cells, and NK-cells.

Hera offers xenograft studies in our SRG rat which provides several advantages over traditional mouse models. It demonstrates high tumor take-rates for difficult cancer types (both PDXs and cell line xenografts), it allows for easier surgical manipulation, increased blood/tissue volume and the ability to combine drug efficacy with metabolism/toxicology endpoints in the relevant Sprague Dawley background. Learn how using the SRG is making oncology studies more reliable, efficient & robust.

Mouse Oncology & Immuno-Oncology Services

Partnering with us not only gives you access to unique SRG rat models but broadens your options with an experienced provider of mouse in vivo services on many backgrounds including NSG, NCG, NOG, and the nude mouse.

Our goal is to deliver the best data possible for our clients. We routinely use both rat and mouse for in vivo oncology and provide advanced immuno-oncology services in mice. Our immune-oncology platform uses mice engrafted with CD34+ hematopoietic stem/progenitor cells (HSPCs), a validated platform providing bone marrow engraftment and development of multi-lineage human immune cells.

We offer standardized humanized mouse models or your specific donor, whether HLA matching or engineered cells for your preclinical studies.

Applications & Case Studies

Find related and up-to-date information and literature for our In Vivo Oncology service
including blogs, posters, presentations, webinars, and white papers.

Accredited Facility Leveraged By Our Talented Team

Located in Lexington, KY, our state-of-the art facility include both our molecular biology laboratory and vivarium from which we provide all our contract research services.

Our barrier status animal facility includes an AAALAC accredited animal welfare program with the Association for Assessment and Accreditation of Laboratory Animal Care, and Hera maintains an OLAW/PHS Assurance (NIH Public Health Service).

To further facilitate comprehensive scientific teams, we hold memberships and training programs with the NIH (National Institute of Health), the University of Kentucky’s Division of Laboratory Animal Resources (DLAR), and the American Association of Laboratory Animal Science (AALAS).

Accelerate Your Pre-Clinical Cancer Research and Drug Development

Contact us to learn more about our CRO services for oncology research.

Xenograft vs PDX

Researchers are often asking our scientific team about how to choose between using a cell line xenograft and a patient derived xenograft (PDX). This article aims to summarize the pros and cons of each approach and allow you to identifying which model type is the best fit for your drug development needs.

The etymology of xenograft begins with Xeno- which is a Latin derived prefix meaning “foreign.” Xenografts can be defined as the transplantation of foreign (i.e. different species) tissue into a recipient host. For oncology studies, this is commonly either an immortalized, homogenous cancer cell line comprising of one cell type or tissue that is collected directly from the cancer patient that includes a heterogenous cell population and transplanted into an animal host. The xenograft host for this type of research is typically an immunodeficient or SCID rodent model, such as the NSG mouse or the SRG rat. When the engraft tissue is sourced directly from the patient and isn’t passaged in cell culture, it is referred to as a patient-derived xenograft (PDX).

Why use a cell line xenograft?

Most preclinical oncology drug efficacy studies are conducted in cell line xenografts because they are more consistent, characterized, and cost effective. Commercially available cell lines (from a repository such as ATCC) are highly standardized allowing for comparisons to data and peer-reviewed publications across the entire field including genotyping and gene expression data. In vitro cell line screens can identify highly susceptible cancer types or particular lines which can be then used implanted as xenografts.

Xenograft cell lines when implanted in rats or mice and generally have high tumor take-rates and growth kinetics across with less study-to-study and animal-to-animal variability. The cell lines characteristics are static and preserved, can be cultured whenever needed, and maintained in repositories providing easy access. This is ideal when compared to a PDX, which requires time and resources to cyrorecover the PDX model or continuously passage in-vivo. PDXs can have more variable tumor uptake and growth kinetics, and their characteristics can drift after multiple passages.

Why use a PDX?

Researchers believe that using a patient derived xenograft model may provide more translatable data by preserving the original tumor complexity and heterogeneity. It has been shown in numerous publications that the original patient tumor heterogeneity is well preserved in initial passages, and PDX treatment data can be more predictive of human drug responses- opening the door to patient-avatar or precision medicine approaches. PDXs often capture rare tumor types, provide interesting mutation profiles, and can answer questions about specific patient populations (to assist in clinical trial enrollment criteria for example).

It has been shown in several publications, including Sato et. al, that at each passage (from animal to animal) the tissue heterogeneity decreases and the number of cell types present, gene expression profiles, and mutation status starts to shift from the original patient sample.

Hera is tackling this problem in two ways:

  1. Using our SRG rat to establish PDXs faster and larger allowing more utility at earlier passages and
  2. Using the rat as xenograft host to address the issue of translatability to the clinic.

Additional disadvantages of PDXs include higher costs, limited access, and longer timelines. Because PDXs are maintained as tumors in a xenograft host and continuously passaged they are costly to maintain or they need to under a cryo-recovery step (3 months). Additionally, each time a PDX is passaged, it needs to be re-characterized to ensure the tumor retains the same mutation profile and histological characteristics.

At Hera, we view PDXs as an extremely important tool to address very specific research questions, or examine patient populations, model rare cancer types, etc, but because of the added cost and timeline, we recommend first demonstrating successful in vivo drug efficacy with a standard cell line xenograft model.

Increasing Translatability

To increase the translatability of drug candidates, Hera recommends using our SRG rat as the xenograft hosts for your research studies. For both cell line xenografts and PDXs our SRG rat has been shown to have a more human-like tumor microenvironment including important difference compared to the mouse in fibrotic tissue and angiogenesis (ask us about it). The rat also has a more human-like drug metabolism leading to translational tumor exposures and prevalence of potential systemic toxicity issues. The SRG rat is highly versatile in many areas of research including drug efficacy, toxicology, and metabolism.

Want to be the first to know about groundbreaking research technology updates?
Subscribe to our mailing list to stay in the know.

Why Rats as a Xenograft Model?

A xenograft model is a surgical graft of tissue from one species to another and commonly utilizes an immunodeficient host animal to prevent transplant rejection. Mice and rats with varying degrees of immune system deficiencies can be used for xenografts, but the preferred model is fully immunocompromised, lacking B-cells, T-cells and natural killer (NK) cells.  Xenografts in these rats and mice of patient derived cells or primary tumor tissues (PDX, PDTT, or PDTX) provide a better model that overcomes the limitations of traditional in-vivo models and more sufficiently represent human cancer characteristics especially with regard to metastasis and drug sensitivity. Patients derived xenografts are being used to provide results with better translational potential that have eluded researchers using traditional rodent models.

Rat models that are B & T-cell deficient (Rag2 KO) or fully immunocompromised (Rag2/Il2rg double KO, lack of B, T and NK-cells) can be used for xenografts, tumor immunology and PDX studies.  Rat models provide several significant advantages for xenograft studies over their complimentary mouse xenografts.

Larger Size:

The larger size of the animals allows for easier handling and more precise surgical manipulations. For example, intracranial xenografts and other orthotopic tissue injections are easier to perform.

More Tissue:

Due to the size of the rats compared to mice, xenograft tumors can grow larger, especially in xenografts into the brain, prostate, and other tissues, and this provides more tissue to analyze.

Easier Tumor Imagining/ Visualization:

Tumor metastasis and angiogenesis are often the primary focus of cancer research and therefore non-invasive in-vivo imagining is becoming an increasingly important tool to understand these aspects of the cancer progression.  Rats have been shown to be a better model for in-vivo imagining of metastatic tumors from xenografts which are easier to detect due to the larger size[4].

More Utility:

The rats can have multiple blood draws, compared to mice, which allow for drug studies and provides more utility.  Additionally, since rats are the preferred model for toxicology, this allows for both efficacy studies and toxicity to be evaluated in the same species.

Sources:

Rat Xenograft Publications

Prostate cancer is the most common cancer and the second leading cause of death from cancer among men in the United States. Many patients who are diagnosed eventually develop castration-resistant prostate cancer (androgen independent) with metastatic foci which are the cause patient death. Therefore, understanding of the mechanisms of the acquisition of metastatic potential or the androgen-independent phenotype of cancer cells is urgently required and in-vivo models which accurately reflect the disease progression are necessary.  Both xenografts and transgenic rodent models of prostate cancer have been established attempting to provide a fast, effective way to recapitulate the human prostate cancer.

Transgenic rodent models that develop prostate cancer due to various genetic modifications provide a relatively reliable model of tumor development proven to be easier to study than carcinogenicity models. However, in the popular TRAMP model it usually takes 24-30 weeks for the adenocarcinomas to develop, the tumors have neuroendocrine features which are rare in human prostate cancers, and they rarely metastasize to distant organs including the bones which is often present in human prostate cancer3. These transgenic models, require a considerable expenditure of time, effort and a large number of animals, and in addition their use has led to few translational outcomes. It is for this reason that xenografts have been a rapidly adopted approach for drug discovery efforts in prostate cancer1-2.

Prostate cancer xenografts provide a way to evaluate potential therapeutics on human cells and to model human tumor progression in vivo1. For these xenografts prostate cancer cells are orthotopically implanted into host animals.  Various xenograft cell lines have been established with different features including those with a high rate of metastasis as well as xenograft lines from human prostate cancer tumors, which are implanted directly into an immunocompromised host, preserving the heterogeneity and eliminating the effects of in vitro culture.  Rats are advantageous due to the larger size of their prostate, because tumors grow larger and provide more tissue for analysis4 and have been used to model various stages of prostate cancer4.

Studies

  1. Pre-clinical mouse models of human prostate cancer and their utility in drug discovery.
    Summary: Xenografts are a particularly useful tool as for evaluating efficacy of investigational new drugs and therapeutic regimens for prostate cancer.  The xenografts in which human tumors are grafted directly into the host animal provide the best recapitulation of the heterogeneity of the human tumors and the eliminates the potential molecular and epigenetic changes that can occur after long periods of in vitro growth.  These patient derived tumor xenografts are already shown to have greater predictability for clinical responses to several pre-clinical drugs.
    Park et al. Current Protocols in Pharmacology. 2010 December 1.  14:14.15.
  2. Animal Models of Human Prostate Cancer: The Consensus Report of the New York Meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee
    Summary: A variety of genetically modified mice for prostate cancer have been developed. These models provide a way to study tumor development in-vivo, however they are costly and it takes a long time to generate results. Xenografts of human prostate cancer cells are a relatively quick and low cost way of studying the biology of human prostate cancer.  The models described in this review have proven useful for evaluating new therapies in prostate cancer and mechanisms of therapeutic resistance.
    Ittmann, et al.  Cancer Research. 2008 May 1. 73, 2718.
  3. Broadening of Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Model to Represent Late Stage Androgen Depletion Independent Cancer
    Summary: The genetically modified spontaneous prostate cancer mouse provides a relevant clinical model for early stages of prostate cancer, but because of a lack of synchronicity and long latent period of tumor incidence/growth, a better in-vivo model is necessary to study the mechanisms of late stages of prostate cancer including metastasis, and androgen independence.
    Jeet, et al. The Prostate.  2008.  68:548 -562.
  4. Establishment of a syngeneic orthotopic model of prostate cancer in immunocompetent rats
    Summary:  An syngeneic orthotopic xenograft line was established as a model for prostate cancer in immunocompetent rats. The aim was to create feasible conditions for anticancer drug development in a species-matched tumor microenvironment of prostate cancer in a model that is most suitable for analysis of stage-specific effects of therapeutic agents. While in some cases species-matched tumors are needed, a fully immunocompromised rat would allow for wide variety of non-species specific and patient derived tumor xenografts providing more utility than the model described.
    Suzuki, et al.  Journal of Toxicologic Pathology.  2015 Jan; 28(1): 21–26.

Breast cancer is the most commonly diagnosed form of cancer and the second leading cause of cancer death in Western women1 . Several difficulties are associated with studying breast cancer, first the different genetic subtypes that have been identified, including triple negative HER2-positive variety, need to be considered when developing a treatment and secondly, breast cancer tumors themselves have been shown to have a high level of heterogeneity. Of the variety of pre-clinical models that have been used to study breast cancer, patient derived tumor xenografts show the most utility for pre-clinical models.

Breast cancer tumor xenografts in mice have been shown to recapitulate all the key characteristics of human breast cancers including histology and pathology, gene expression profiles, and for estrogen receptor positive tumors, estrogen dependence and/or responsiveness.  These have been shown to preserve the heterogeneity of the original tumor as well.  Other models such as synergenic models (allografts) of breast cancer have limited potential for direct translation into clinical application due to species-related differences.

Using rats for the study of breast cancer, provides several advantages. -It has been shown that there are many histological similarities that have been demonstrated between rat mammary tumors and human breast cancers.  Rats are also larger and provide a better model for in-vivo imaging to study cancer metastasis and angiogenesis.  In addition, the carcinogenic rat models in which chemically induced tumors are used to study tumorigenesis have been used historically because of the ease with which hormone dependent tumors can be generated by carcinogens1 and this research provides a background for a more critical understanding of xenograft/host interactions.

Studies:

  1. Models of breast cancer: is merging human and animal models the future?
    Summary:  The most widely used syngeneic mouse tumor models have a limited role in cancer research because the biology of rodents and their tumors differs significantly from that of humans and human breast cancer. While breast cancer is one of the more difficult tumors to transplant, human xenograft models have the potential to be a good model for preclinical testing.
    Kim, et al.  Breast Cancer Research.  2004. 6:1, 22-30.
  2. Animal models for breast cancer
    Summary:  Carcinogen-induced mammary tumors in rats can be used as a tool for studying tumorigenesis and breast cancer progression and metastasis.  The rat is the preferred model for carcinogen induced breast cancer because of the ease at which hormone-dependent tumors can generated. The tumors progress from preneoplastic, neoplastic, to metastatic tissues allowing the study of events in the tumorigenic process.
    Sukumar, et al. Mutation Research.  1995 December.  333:2, 37-44.
  3. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis, and disease outcomes.
    Summary:  Transplantable breast cancer tumors derived directly from patients are shown to represent the diversity of human breast cancer and maintain the essential features of the original patients’ tumors. These tumor grafts are shown to have a high potential for clinical relevance and ease of use which will prove to be an excellent model for breast cancer researchers. Successful tumor engraftments in the NOD/SCID mouse was found to be about 30%  and this could possibly be improved by using a fully immunocompromised host for the tumor transplantation.
    DeRose, et al.  Nature Medicine.  2011 October 23. 17:11, 1514-1520.
  4. Establishment of a Lung Metastatic Breast Tumor Xenograft Model in Nude Rats.
    Summary:  This paper demonstrated the establishment of a xenograft breast cancer line that metastasizes to the lungs, this xenograft model was developed in response to the need for a better in-vivo imaging model.  Rats, due to their larger size, provide a model with a for studying spontaneous metastasis using non-invasive magnetic resonance imaging (MRI) with a high potential to translate to human imaging.  Rats were also chosen as due to the histological similarities that have been demonstrated between rat mammary tumors and human breast cancers.
    Nofiele, et al.  PLoS ONE.  2014 May 16. 9(5), e97950.
  5. A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone
    SummaryStudying metastasis of breast cancer with humanized xenograft models incorporating human cells or tissue grafts at the primary tumor site or the metastatic site mimic the human disease more closely. It is for these reasons that humanizations are currently being developed.  Immunocompromised rats would lend themselves to being humanized comparable to the mice models described, but their larger size would confer significant advantages.
    Thibaudeau, et al.  Disease Models and Mechanisms.  2014. 7, 299-309.
  1. A reproducible brain tumor model established from human glioblastoma biopsies
    Summary: Xenografts of patient biopsy spheroids of glioblastoma tumors where transplanted into nude rats with a high success rate of engraftment. The larger size of the rat brain allows for easier injections and allows for other procedures and experiments which are limited in mice.
    Huszthy, et al.  PLoS ONE, 2015 August.  10(8), e0136089.
  2. Experimental model and immunohistochemical analyses of U87 human glioblastoma cell xenografts in immunosuppressed rat brains
    Summary: A glioblastoma cell line used for xenografts was validated as a cost effective and simple approach to studying glioblastoma. This model was demonstrated to have a high take rate for xenograft implants. In this model, the rats used are immunosuppressed with cyclosporine. However, since the development of genetically modified rats which have immune deficiencies, the immunosuppression step can be eliminated.
    Strojnik, et al. Anticancer research.  2006.  vol.26(4B), pp.2887-900
  1. Orthotopic Human Choroidal Melanoma Xenografts in Nude Rats with Aggressive and Nonaggressive PAS Staining Patterns
    Choroidal melanoma is the most common primary ocular cancer among adults. This study describes a human choroidal melanoma orthotopic xenograft model developed in nude rats.   The xenografts in nude rats reproduced the PAS staining patterns associated with aggressive and non-aggressive choroidal melanomas in patients.  The rat was chosen as the model because in mice the injections are difficult and the tumors can’t be visualized due to the small size, rabbits are another option but they are required to be kept on immunosuppressant’s, are costly to maintain, have a limited availability of antibodies for immunohistochemical studies.
    Braun, R. D., & Abbas, A. Investigative Ophthalmology & Visual Science, 47(1), 7–16.

Ready To Advance Your Research?

Let’s Talk