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A Vascular Model of Tsc1 Deficiency Accelerates Renal Tumor Formation with Accompanying Hemangiosarcomas

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A Vascular Model of Tsc1 Deficiency Accelerates Renal Tumor Formation with Accompanying Hemangiosarcomas Published OnlineFirst December 29, 2014; DOI: 10.1158/1541-7786.MCR-14-0178 Oncogenes and Tumor Suppressors Molecular Cancer Research A Vascular Model of Tsc1 Deficiency Accelerates Renal Tumor Formation with Accompanying Hemangiosarcomas Jarrett D. Leech1, Stephen H.T. Lammers1, Sam Goldman1, Neil Auricchio2, Roderick T. Bronson3, David J. Kwiatkowski2, and Mustafa Sahin1 Abstract Tuberous sclerosis complex (TSC) is an autosomal disease sarcomas and kidney cystadenomas were responsive to intra- caused by inactivating mutations in either of the tumor peritoneal rapamycin treatment. Immunoblotting and immu- suppressor genes TSC1 or TSC2. TSC-associated tumor growth nostaining for phospho-S6 (pS6) and phospho-CAD showed is present in multiple tissues and organs including brain, that the effect of rapamycin on tumor size was through kidney, liver, heart, lungs, and skin. In the kidney, TSC inhibition of the mTOR signaling pathway. Finally, elevated angiomyolipomas have aberrant vascular structures with VEGF mRNA levels were also observed in hemangiosarcoma abnormal endothelial cells, suggesting a role for endothelial specimens. Because paw hemangiosarcomas are easily detect- mTORC1 function. In the current report, a genetically engi- able and scorable for size and growth, this novel mouse neered mouse model (GEMM) with a conditional knockout model enables accelerated in vivo drug testing for therapies allele of Tsc1 with a Darpp32-Cre allele displayed accelerated of TSC-related tumors. formation of both kidney cystadenomas and paw hemangio- sarcomas. All mutant mice developed hemangiosarcomas on Implications: These findings provide a strong rationale for simul- multiple paws by 6 weeks of age. By 16 weeks of age, the taneous use of this conditional knockout mouse as an in vivo average mutant hind paw was 4.0 mm in diameter, nearly genetic model while seeking new cancer therapies for TSC-related double the size of control mice. Furthermore, the hemangio- tumors. Mol Cancer Res; 13(3); 548–55. Ó2014 AACR. Introduction TSC are of a benign phenotype (4). However, renal angiomyoli- pomas can proliferate, and subsequent renal complications are Tuberous sclerosis complex (TSC) is a genetic disorder due to an cited as the most common cause of death in adult patients with inactivating mutation in either TSC1 or TSC2. The protein products TSC. Thus, therapies that inhibit hyperactive mTOR pathway are of TSC1 and TSC2, hamartin and tuberin, respectively, form a candidates for treatment of TSC-related tumors. heterodimeric complex that inhibits the mTOR complex 1 (mTOR) Rapamycin and related compounds (rapalogues) have been pathway via RHEB-GTP modulation (1, 2). Activation of mTOR studied with regard to the inhibition of mTOR and treatment of primarily regulates cell size and proliferation through promotion TSC-related tumor growth (3, 6). In multiple murine models of of translation (1). Germline TSC1 or TSC2 mutations are com- TSC, treatment of TSC-related tumors is effective in reducing plemented by second-hit loss of the wild-type allele leading to tumor size (7–9). Clinically, rapalogue treatment has been shown hyperactive mTOR activity, which results in the growth of tumors in to result in regression of both renal angiomyolipomas (10, 11) brain (subependymal nodules and giant cell astrocytomas), kidney and subependymal giant cell astrocytomas (12, 13). However, (renal angiomylipoma), and lung (pulmonary lymphyangioleio- rapalogue treatment does not lead to tumor elimination, and myomatosis; refs. 3–5). In addition to tumor growth, a combina- cessation of treatment results in re-growth of tumors (10, 13, 14). tion of intellectual disability, epilepsy, and autism occurs in a Other drawbacks to the use of rapamycin are side effects ranging majority of individuals with TSC (2). Most tumors that arise due to from diarrhea, stomatitis, respiratory infection, and pyelonephri- tis (10). Hence, identification of more efficacious therapies is desirable to further the treatment of TSC-related tumor growth 1Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts. 2Department of and subsequent clinical management. Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Both cell-based and animal models have been used to identify 3 Department of Microbiology and Immunobiology, Harvard Medical therapeutics for treatment of TSC-related tumors (15). However, School, Boston, Massachusetts. þ À þ À both Tsc1 / and Tsc2 / mice develop kidney cystadenomas and Note: Supplementary data for this article are available at Molecular Cancer liver hemangiomas as their main phenotype, tumors which do not Research Online (http://mcr.aacrjournals.org/). match the pathology of human TSC (16–18). Furthermore, the Corresponding Author: Mustafa Sahin, Boston Children's Hospital, Department of development of kidney and liver tumors in murine models can Neurology, 300 Longwood Avenue CLS14073, Boston, MA 02115. Phone: 1-617- take from 4 to 15 months of age with varying incidence rates 919-4518; Fax: 1-617-730-0279; E-mail: [email protected] (17, 18). In the present study, by combining a conditional knock- doi: 10.1158/1541-7786.MCR-14-0178 out allele of Tsc1 with a Darpp32-Cre allele, we created a mouse Ó2014 American Association for Cancer Research. that develops kidney cystadenomas and hemangiosarcomas in the 548 Mol Cancer Res; 13(3) March 2015 Downloaded from mcr.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst December 29, 2014; DOI: 10.1158/1541-7786.MCR-14-0178 Novel Tsc1 Darpp-32 Cre In Vivo Tumor Model extremities on an accelerated time scale. Furthermore, we tracked er. Protein concentrations were determined by Bradford Assay paw hemangiosarcoma development by simple observation dur- (BioRad Laboratories), equal concentrations were separated by ing rapamycin treatment, demonstrating its use as an easily scor- electrophoresis on 6%–12% Bis–Tris acrylamide gels and able measure of tumor response. Our results demonstrate the then transferred onto Immobilon-P PVDF membranes (EMD usefulness of this model for preclinical testing of novel drugs for Millipore). Membranes were blocked with 5% nonfat dry milk the treatment of TSC-related tumors. in 1Â TBST (Tris-buffered saline and 10% Triton-X) for 1 hour at room temperature. Primary antibodies were diluted in 5% nonfat Materials and Methods dry milk or 5% bovine serum albumin in 1Â TBST and applied Breeding strategy and phenotyping to the membranes overnight at 4 C. Primary antibodies included All animal procedures and protocols were approved by the P-CAD (Cell Signaling), CAD (Cell Signaling), p-S6-240 (Cell Institutional Animal Care and Use Committee (IACUC) and Signaling), S6-240 (Cell Signaling), and anti-tubulin (Abcam). Animal Resources at Children's Hospital (ARCH). Mouse experi- After primary antibody incubation and washing with 1Â TBST, ments were performed on a mixed strain background. Mice anti-mouse (Santa Cruz), or anti-rabbit (Rockland) horseradish bearing the loxP-flanked Tsc1 allele (Tsc1c/c; ref. 19) were bred peroxidase (HRP)-conjugated secondary antibodies were applied with mice bearing the Darpp-32 Cre allele, with further matings for 1 hour at room temperature in 5% nonfat dry milk solution of cc to generate Tsc1 Darpp-32 Creþ male mice (20). All other 1Â TBST. Supersignal West Pico and Dura Chemiluminescent non-mutant male genotypes were used as littermate controls (Thermo Fisher Scientific) signal solutions were used to detect cw ww (Tsc1 and Tsc1 ). Genotyping for lox-p sites for Tsc1 and for antibody binding and signals were collected using an ImageQuant the Darpp-32 Cre was performed with standard PCR. Primers LAS 2000 imager (GE Healthcare). F4530 (05- AGGAGGCCTCTTCTGCTACC-30) and R4380 (05- CAGCTCCGACCATGAAGTG-30) were used for Tsc1 and Cre F Immunohistochemistry (05-GGACATGTTCAGGGATCGCCAGGCG-30 and Cre R (05-GC- Immunohistochemical analyses were performed on paraffin- ATAACCAGTGAAACAGCATTGCTG-30) were used for the detec- embedded sections of kidney and paw after 4% paraformalde- tion of the Darpp-32 Cre. hyde fixation for 12 hours or on frozen OCT-embedded tissues following 4% paraformaldehyde fixation. Phospho-S6 Ser 240/ Tumor measurements 244 (Cell Signaling, Cat. No: 2215) was used as a primary An observer (S. Goldman) blind to the genotype performed antibody at 1:500 dilution. Secondary antibodies included Alexa paw measurements. Hind paw diameter was measured using a Fluor 488 anti-goat and anti-rabbit used at 1:500 dilution. For X- 0.1-mm resolution caliper in the plantar to dorsal dimension. gal staining, tissue was harvested and fixed with 4% paraformal- Mean paw diameters were determined by the average of both left dehyde overnight, followed by standard sucrose cryopreservation and right paws. Paw diameters were measured biweekly until and OCT embedding. Sections were sliced and then stained in death. Individual mice were euthanized when paw diameter of 5 X-gal staining solution overnight at 37C followed by counter- mm, weight loss of 20%, or greatly extreme lethargy was seen. staining with Nuclear Fast Red as previously described (21). Treatment protocol qPCR All mouse treatments commenced when the diameter of rear All tissue samples from kidney and paws were extracted 1 week paw tumors averaged 4.0 mm. Mice treated with rapamycin (LC after the last day of treatment in a sterile fashion and immediately Laboratories, Cat. No: R-5000) were injected
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