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Histological sections of a human malignant melanoma, SSX, before (left panel) and 6 days after (right panel) implantation under the renal capsule of immunocompetent mice. (H & E x 620).
Source publication
Human tumour lines established in athymic nude mice were grafted under the renal capsule of immunocompetent mice. Grafts from 27 human tumour lines comprising 9 malignant melanomas, 10 sarcomas, 2 colon carcinomas, 4 lung carcinomas and 2 mammary carcinomas, grew well under the renal capsule of the immunocompetent mice and retained morphological an...
Context in source publication
Context 1
... sections of the subrenal grafts on Day 6 were compared with sections of the corresponding subcutaneous tumours in nude mice. In Figure 3 histological sections are shown of an amelanotic malignant melanoma, grown in nude mice and of the corresponding subrenal tumours on Day 6. Comparison of the sections before and after growth under the renal capsule shows that the subrenal graft contained undifferentiated polygonal cells with abundant cytoplasm, a picture almost identical with that of the original tumour. ...
Citations
... DST can be performed in vivo or in vitro by comparing the therapeutic efficacies of candidate drugs against surgically removed tumor to identify optimal drug selection. For in vivo DST, tumors are xenografted into immune-deficient mice, and drug treatments are applied and evaluated [9,10]. DST in vivo is labor intensive, expensive, and technically demanding, which limits its clinical application. ...
A novel anti-cancer drug sensitivity testing (DST) approach was developed based on in vitro single-cell Raman spectrum intensity (RSI). Generally, the intensity of Raman spectra (RS) for a single living cell treated with drugs positively relates to the sensitivity of the cells to the drugs. In this study, five cancer cell lines (BGC 823, SGC 7901, MGC 803, AGS, and NCI-N87) were exposed to three cytotoxic compounds or to combinations of these compounds, and then they were evaluated for their responses with RSI. The results of RSI were consistent with conventional DST methods. The parametric correlation coefficient for the RSI and Methylthiazolyl tetrazolium assay (MTT) was 0.8558 ± 0.0850, and the coefficient of determination was calculated as R2 = 0.9529 ± 0.0355 for fitting the dose–response curve. Moreover, RSI data for NCI-N87 cells treated by trastuzumab, everolimus (cytostatic), and these drugs in combination demonstrated that the RSI method was suitable for testing the sensitivity of cytostatic drugs. Furthermore, a heterogeneity coefficient H was introduced for quantitative characterization of the heterogeneity of cancer cells treated by drugs. The largest possible variance between RSs of cancer cells were quantitatively obtained using eigenvalues of principal component analysis (PCA). The ratio of H between resistant cells and sensitive cells was greater than 1.5, which suggested the H-value was effective to describe the heterogeneity of cancer cells. Briefly, the RSI method might be a powerful tool for simple and rapid detection of the sensitivity of tumor cells to anti-cancer drugs and the heterogeneity of their responses to these drugs.
... A variety of transplantation sites are available in the mouse, and several have been used in attempts to generate breast cancer PDX models. Tissue can be transplanted into the anterior compartment of the eye [146,147], under the renal capsule [148][149][150][151], within the intrascapular fat pad [68], subcutaneously (ear, flank, etc.), or orthotopically within the mammary fat pad (either the intact (IFP) or epithelium-free Bcleared^(CFP) fat pad) [152] or injected into the mammary ducts themselves [153,154,141]. ...
Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and “Triple-negative” (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward “credentialing” of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research.
... Subsequently, on days 4, 8, and 12 after grafting, five mice in each group were euthanized under anesthesia and the kidneys were removed and the grafts were measured in situ by using a stereoscopic microscope, fitted with an ocular micrometer, and calibrated in ocular units (OMU, 1OOMU = 1 mm) to examine tumor growth. Two perpendicular diameters were measured and the difference in mean tumor diameter was calculated [26]. ...
... 5 × 10 6 SKOV3 cells, which formed tumors in nude mice, were injected subcutaneously into α1,3GT KO female mice, however, no macroscopic tumor developed. It was reported that human tumor xenografts, including tumors that had been established in serial transplantation in athymic nude mouse hosts or primary surgical tumor tissues, implanted under the renal capsule of normal mice were quantifiable in ocular micrometer units for six days and could retain morphological and functional characteristics of the parent tumors [26,52]. So we administered injections of SKOV3 cells s.c. ...
Background:
As ovarian cancer stem cells (CSCs) are responsible for tumor initiation, invasion, metastasis, and chemo-resistance, new stratagems that selectively target ovarian CSCs are critically significant. Our previous work have demonstrated that ovarian cancer spheroid cells are tumorigenic and chemo-resistant, and have the properties of ovarian CSCs. Herein, we hypothesized that expressing α-gal epitopes on ovarian spheroid cells may help eliminate CSCs and improve the outcome of therapeutic intervention for ovarian cancer patients.
Methods:
Lentivirus-mediated transfer of a pig α(1,3)galactosyltransferase [α1,3GT] enzyme gene into human ovarian cell line SKOV3 cells formed α-gal epitope-expressing cells (SKOV3-gal cells), and then these cells were maintained in a serum-free culture system to form SKOV3-gal spheroid cells. Efficacy of this cell vaccine was demonstrated in α1,3GT knockout mice (α1,3GT KO mice).
Results:
The antibody titers to α-gal epitopes measured by ELISA were significantly increased in α1,3GT KO mice after immunization with SKOV3-gal spheroid cells. Furthermore, compared with the non-immunized KO mice, the SKOV3 tumors grafted under renal capsules of KO mice immunized with SKOV3-gal spheroid cells grew slower and began to shrink on day 12. Western blot analysis also showed that immunized KO mice can produce effective antibody against certain tumor associated antigens (TAAs) derived from both SKOV3 cells and SKOV3 spheroid cells. The TAAs were further investigated by mass spectrometry and RNA interference (RNAi) technology. The results suggested that antibodies responding to protein c-erbB-2 may be raised in the sera of the mice after immunization with SKOV3-gal spheroid cells. Ultimately, vaccination with SKOV3-gal spheroid cells induced more CD3 + CD4 + T cells in the spleen of immunized mice than non-immunized KO mice.
Conclusions:
The results suggest that vaccination using ovarian cancer stem-like cells engineered to express α-gal epitopes may be a novel strategy for treatment of ovarian cancer.
... The basic procedures and schedules of in vivo DST of cancer therapy are to transplant human tumor tissues into the bodies of some types of immuno-deficient mice (athymic nude mice or severe complicated immune-deficient mice, SCID mice etc) [13][14][15][16][17][18]. Afterwards, drug therapeutic efficacies to these tumor-bearing mice are recorded and calculated. ...
... The subrenal capsule (SRC) assay [13][14][15][16][17][18] is the earliest in vivo DST method. It involves transplanting surgically removed tumors into the renal capsules of mice-evaluating and testing the candidate anticancer drug inhibitory responses to tumor cells and tissues within 4-11 days. ...
... Despite approximately 80% positive relationship between DST and clinical chemotherapeutic efficacy (partial response PR or complete response CR), most clinical data show that only less than 25-35% clinical data report improvement in cancer patients' survival by using DST. In most cases, patients' survival is almost the same in spite of using in vitro and in vivo DST [5][6][7][8][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. Possible reasons behind the scenes can be speculated into the following three possibilities; 3. Chemotherapy does not target on neoplasm metastases or cancer stem cells [5][6][7][8]. ...
Clinical cancer treatment and therapy have been gradually improved by experimental and clinical advancements worldwide, especially after the advent of different types of individualized cancer therapy (ICT) and new generations of anticancer drugs. Despite the long history of anticancer drug sensitivity testing (DST), its therapeutic benefits to clinical cancer patients are compromised and controversial. DST techniques are diversified and improved a great deal, but they have not been developed into an overwhelming means to cure all cancer patients in clinics. The retrospection and panorama of historic and evolutionary developments of DST including clinical relevance, advantageous, technical cautions, limitations or even shortcomings of varied models and methodologies at present stage are addressed. Possible future directions and novel ideas are also discussed and highlighted.
... Szot et al. (2007) have recently illuminated renal capsule xenografting of pancreatic islets 9 . Aamdal et al. (1985) described renal capsule xenografting of 27 human cancer cell lines in immunocompromised mouse hosts 10 . Grafts can also be composed of a single immortalized cell line (cancerous or nontumorigenic), or can consist of an immortalized cell line combined with cells isolated from mesenchyme (cell recombinant graft). ...
... Szot et al. (2007) have recently illuminated renal capsule xenografting of pancreatic islets 9 . Aamdal et al. (1985) described renal capsule xenografting of 27 human cancer cell lines in immunocompromised mouse hosts 10 . Grafts can also be composed of a single immortalized cell line (cancerous or nontumorigenic), or can consist of an immortalized cell line combined with cells isolated from mesenchyme (cell recombinant graft). ...
New therapies for two common prostate diseases, prostate cancer (PrCa) and benign prostatic hyperplasia (BPH), depend critically on experiments evaluating their hormonal regulation. Sex steroid hormones (notably androgens and estrogens) are important in PrCa and BPH; we probe their respective roles in inducing prostate growth and carcinogenesis in mice with experiments using compressed hormone pellets. Hormone and/or drug pellets are easily manufactured with a pellet press, and surgically implanted into the subcutaneous tissue of the male mouse host. We also describe a protocol for the evaluation of hormonal carcinogenesis by combining subcutaneous hormone pellet implantation with xenografting of prostate cell recombinants under the renal capsule of immunocompromised mice. Moreover, subcutaneous hormone pellet implantation, in combination with renal capsule xenografting of BPH tissue, is useful to better understand hormonal regulation of benign prostate growth, and to test new therapies targeting sex steroid hormone pathways.
... But since nude or ACID mice are difficult to breed and maintain, it seems a financial burden for a patient to use them for drug sensitivity tests. So a 4-day or 6-day subrenal capsule assay procedures (SRCP) using normal immunocompetent mice were suggested as a superseded method to do this task (Bogden AE et al., 1979;Levi FA et al., 1984;Aamdal S et al., 1985;Cunningham D et al., 1986). But there are many unanswered questions about this substitution and further work are needed to perfect them. ...
... There is a widely accepted concept to use immuno-competent mice in SRCP in drug sensitivity tests. In the previous work, the comparisons were based between the data of 4-days or 6-days SRCP in normal mice with 11-days SRCP in nude mice (Bogden AE et al., 1978;Stratton JA et al., 1984;Bogden AE et al., 1979;Levi FA et al., 1984;Aamdal S et al., 1985;Cunningham D et al., 1986). So there is no general conclusion of which is the best. ...
... Specific NK cell depletion strategies have been employed using antibodies specifically directed against antigens expressed by NK cells [anti-asialo-GM1 (AA-GM1) and anti-NK1.1 antibodies]. Although AA-GM1 can inhibit NK cell activity in vitro and in vivo [57 -59], its influence on the survival of NK-resistant lymphoma cells in nude mice is controversial [60]. Other studies have shown very little additional benefit of immunosuppression with the addition of anti-asialo-GM1 antibodies in irradiated mice, especially in the profoundly immunosuppressed NOD/SCID strain [28]. ...
The lymphomas probably represent the most complex and heterogenous set of malignancies known to cancer medicine. Underneath the single term lymphoma exist some of the fastest growing cancers known to science (i.e Burkitt's and lymphoblastic lymphoma), as well as some of the slowest growing (i.e. small lymphocytic lymphoma [SLL] and follicular lymphoma). It is this very biology that can dictate the selection of drugs and treatment approaches for managing these patients, strategies that can range from very aggressive combination chemotherapy administered in an intensive care unit (for example, patients with Burkitt's lymphoma), to watch and wait approaches that may go on for years in patients with SLL. This impressive spectrum of biology emerges from a relatively restricted number of molecular defects. The importance of these different molecular defects is of course greatly influenced by the intrinsic biology that defines the lymphocyte at its different stages of differentiation and maturation. It is precisely this molecular understanding that is beginning to form the basis for a new approach to thinking about lymphoma, and novel approaches to its management. Unfortunately, while our understanding of human lymphoma has blossomed, our ability to generate appropriate animal models reflective of this biology has not. Most preclinical models of these diseases still rely upon sub-cutaneous xenograft models of only the most aggressive lymphomas like Burkitt's lymphoma. While these models clearly serve an important role in understanding biology, and perhaps more importantly, in identifying promising new drugs for these diseases, they fall short in truly representing the broader, more heterogenous biology found in patients. Clearly, depending upon the questions being posed, or the types of drugs being studied, the best model to employ may vary from situation to situation. In this article, we will review the numerous complexities associated with various animal models of lymphoma, and will try to explore several alternative models which might serve as better in vivo.
... Another improvement was the utilization of the renal capsule graft site, which provides one of the most vasculogenic sites for transplantation, thus resulting in a high take-rate and optimal growth. The renal capsule site has been used for growth of rat pancreatic islets (Reece-Smith et al. 1981), mouse neural lobes (Stach-Chilf et al. 1981), human gliomas (Weizsacker et al. 1983), human tumor xenografts (Aamdal et al. 1985), human fetal mammalian reproductive tract (Taguchi et al. 1984), mouse mammary glands (Wiesen et al. 1999) and a variety of other cells and tissues. Incorporating these modifications, a novel method was used to grow human breast epithelium in vivo, using organoids from reduction mammoplasties combined with either mouse or human mammary fibroblasts embedded in a collagen gel that was transplanted under the renal capsule of female nude mice (Parmar et al. 2002). ...
This review deals with the development and hormonal responses of mouse and human mammary glands. A major focus of the review is the role of mesenchymal-epithelial interactions in embryonic mammary development and the role of stromal-epithelial interactions in mammary gland biology. Finally, we present a new model for studying growth, differentiation and hormonal response in human breast epithelium grown in vivo in nude mouse hosts. This new model involves the construction of tissue recombinants composed of human or mouse mammary fibroblasts plus human breast epithelium in polymerized collagen gels. In the model, mouse mammary fibroblasts and human breast fibroblasts appear to support the normal differentiation and growth of human breast epithelium equally. This observation raises the possibility of using mouse mammary fibroblasts from various mutant mice to assess the role of specific paracrine-acting gene products in human mammary gland biology and carcinogenesis.
... Another improvement was the utilization of the renal capsule graft site, which provides one of the most vasculogenic sites for transplantation, thus resulting in a high take-rate and optimal growth. The renal capsule site has been used for growth of rat pancreatic islets (Reece-Smith et al. 1981), mouse neural lobes (Stach-Chilf et al. 1981), human gliomas (Weizsacker et al. 1983), human tumor xenografts (Aamdal et al. 1985), human fetal mammalian reproductive tract (Taguchi et al. 1984), mouse mammary glands (Wiesen et al. 1999) and a variety of other cells and tissues. Incorporating these modifications, a novel method was used to grow human breast epithelium in vivo, using organoids from reduction mammoplasties combined with either mouse or human mammary fibroblasts embedded in a collagen gel that was transplanted under the renal capsule of female nude mice (Parmar et al. 2002). ...
The Sonic hedgehog (SHH)-signalling pathway mediates epithelial-mesenchymal interactions in several tissues during development and disease, and we have investigated its role in rat ventral prostate (VP) development. We have demonstrated that Shh and Ptc expression correlates with growth and development of the prostate and that their expression is not regulated by androgens in the VP. Prostatic budding was induced in response to testosterone in Shh null mouse urogenital sinus (UGS) explants grown in vitro and in rat UGS explants cultured with cyclopamine, suggesting that SHH-signalling is not critical for prostatic induction. SHH-signalling was disrupted at later stages of VP development (in vitro), resulting in a reduction in organ size, an increase in ductal tip number, and reduced proliferation of ductal tip epithelia. The addition of recombinant SHH to VPs grown in vitro caused a decrease in ductal tip number and expansion of the mesenchyme. In the presence of testosterone, inhibition of SHH-signalling accelerated the canalisation of prostatic epithelial ducts and resulted in ducts that showed morphological similarities to cribiform prostatic intraepithelial neoplasia (PIN). The epithelia of these ducts also demonstrated precocious and aberrant differentiation, when examined by immunohistochemistry for p63 and cytokeratin 14. In conclusion, we show that SHH-signalling is not essential for prostatic induction, but is important for prostatic growth, branching, and proliferation, and that androgen-stimulated growth in the absence of signalling from the SHH pathway results in aberrant epithelial differentiation.
... The subcapsular renal xenograft (SRC) model was used to evaluate the anti-tumor activity of liposomes. Since Aamdal et al. reported that many human tumors grow well and retain the morphology and characteristics of the parent tumors in the SRC model, 13) we adopted the SRC model for studying the antitumor effect depending on the antibody and the antigen interaction. SRC tumors were also obtained to prepare paraffinembedded sections for immunohistochemistry with GAH. ...
... We here examined the effect of cancer-specific-antibody conjugation onto PLD on the antitumor efficacy against human colorectal cancers using the SRC model, in which many human tumors grow well and retain the morphology and characteristics of the parent tumors. 13) In agreement with our previous results using a stomach cancer cell line in SRC and SC (subcutaneous) models, 12) MCC-456 showed strong antitumor activity against GAH-reactive colorectal cancers compared to free DXR or PLD. ...
MCC-465 is an immunoliposome-encapsulated doxorubicin. The liposome is tagged with polyethylene glycol and the F(ab')2 of a monoclonal antibody named GAH, a human antibody obtained by the hybridoma technique. The epitope recognized by GAH is not well characterized, but human gastric, colorectal, and mammary cancer cells were GAH-positive, while the normal counterparts were GAH-negative. Pegylated liposome doxorubicin (PLD) and MCC-465 did not show significant antitumor activity against GAH-negative Caco-2 xenografts. On the other hand, MCC-465 exhibited significantly superior antitumor effects against GAH-positive WiDr-Tc and SW837 xenografts, compared with PLD. Immunohistochemistry with GAH revealed that 94% (100 of 106) of surgical specimens of colorectal cancer were GAH-positive. These results warrant a phase I clinical trial of MCC-465 for patients with metastatic colorectal cancer.
