Muscle Sarcoma Research Articles

Functional reconstruction of the deltoid muscle following complete resection of musculoskeletal sarcoma

Although the deltoid muscle has been assumed to be an essential shoulder muscle, the full extent of postoperative functions of the upper extremity following its complete resection due to sarcoma has not been thoroughly investigated. In this study, we review patients who underwent wide resection for sarcoma in the deltoid muscle, followed by functional reconstruction using pedicled latissimus dorsi (LD) muscle transfer. Four patients with sarcoma arising in the deltoid muscle were reviewed. Tumor resection with a wide surgical margin resulted in loss of the entire deltoid muscle together with the axillary nerve. For reconstruction, the ipsilateral pedicled LD muscle was transferred on its neurovascular pedicle for use as a functional substitute. One case had local recurrence and the transferred LD myocutaneous flap was resected. There were no serious complications after the operation, and all flaps survived perfectly. Wound healing at both the recipient and donor sites was uneventful. Active abduction of the shoulder joint was >160° in all patients. The muscle manual test of shoulder flexion was good to normal and abduction was fair to good. Musculoskeletal Tumor Society scores were excellent in all cases and the average score was 92% (range, 87-93%). Our results suggest that removal of the entire deltoid muscle resulted in a slight impairment of function. Pedicled LD musculocutaneous flaps are useful for covering the defect that results from resection of the deltoid muscle and they contribute additional function to the affected shoulder.

Alveolar rhabdomyosarcoma–associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression

Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the paired box 3-forkhead box protein O1 (PAX3-FOXO1) fusion oncogene. Despite its discovery nearly two decades ago, the mechanisms by which PAX3-FOXO1 drives tumor development are not well characterized. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence checkpoints. We have now found that this bypass occurs in part through PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member. RASSF4 expression was upregulated in PAX3-FOXO1-positive aRMS cell lines and tumors. Enhanced RASSF4 expression promoted cell cycle progression, senescence evasion, and tumorigenesis through inhibition of the Hippo pathway tumor suppressor MST1. We also found that the downstream Hippo pathway target Yes-associated protein 1 (YAP), which is ordinarily restrained by Hippo signaling, was upregulated in RMS tumors. These data suggest that Hippo pathway dysfunction promotes RMS. This work provides evidence for Hippo pathway suppression in aRMS and demonstrates a progrowth role for RASSF4. Additionally, we identify a mechanism used by PAX3-FOXO1 to inhibit MST1 signaling and promote tumorigenesis in aRMS.

Synovial sarcoma of the spine: a case involving paraspinal muscle with extensive calcification and the surgical consideration in treatment

Synovial sarcoma is a rare malignant tumor of the spine. This tumor may present as a painless mass of the spine or slowly enlarge, causing pain or neurologic deficits. As it is difficult to differentiate this lesion from other soft tissue tumors, synovial sarcoma requires histologic confirmation for definite diagnosis. Thus, the treatment strategy is often planned in the final step depending on the pathologic results. Despite its rare incidence, a few cases of primary or metastatic synovial sarcoma involving the spinal cord, foramen, vertebral body, or paraspinal muscles have been reported in the literature. We present the case of a 29-year-old man with a synovial sarcoma in the paraspinal muscle of the cervical spine. The patient was evaluated radiologically and histologically. Plain radiography, computed tomography, and magnetic resonance imaging were performed as part of the preoperative workup, and immunohistochemical and cytogenetic studies were additionally performed to identify the histologic features of the tumor. The patient underwent marginal resection followed by adjuvant radiation therapy. The patient has been followed up for 2 years. This article highlights the features of synovial sarcoma of the spine via a comprehensive review. Synovial sarcoma of the spine is uncommon, but it is a challenging issue in both diagnostic and therapeutic aspects. The currently available evidence suggests the use of a multidisciplinary approach in the treatment of synovial sarcoma, which includes complete resection and radiation therapy.

Limb function after excision of a deltoid muscle sarcoma

Limb function after excision of deltoid muscle sarcomas has not been thoroughly investigated, although a large defect of soft tissue often causes some degree of dysfunction after wide excision. We formulated a hypothesis that the limb functional results depend on the volume of the excised deltoid muscle and examined the clinical outcomes in patients with a sarcoma in the deltoid muscle treated by surgical resection. The clinical outcomes of 8 patients with a malignant soft tissue tumor in the deltoid muscle were retrospectively reviewed. The following items were evaluated: type of excision of the deltoid muscle, including total excision, subtotal excision, and partial excision; surgical margins; reconstruction procedure used; postoperative complications; local recurrence; metastasis; survival; and functional results (determined by the Musculoskeletal Tumor Society scoring system). After surgical resection, reconstruction in 6 of 8 patients was performed by pedicled latissimus dorsi musculocutaneous or muscle flap or pedicled trapezius musculocutaneous flap. Two patients did not undergo reconstruction because skin closure was possible. The partial excision group had a Musculoskeletal Tumor Society score of 100.0%, and the subtotal excision case and the total excision group had scores of 76.6% and 82.2%, respectively. None of the patients has demonstrated any evidence of local recurrence. We conclude that the functional results may depend on the volume of the excised deltoid muscle. Latissimus dorsi and trapezius musculocutaneous flaps were found to be useful for covering a defect of the deltoid muscle, although these flaps did not contribute to function of the shoulder.

Cyclin-Dependent Kinase 4 Phosphorylates and Positively Regulates PAX3-FOXO1 in Human Alveolar Rhabdomyosarcoma Cells

Alveolar rhabdomyosarcoma (ARMS) is an aggressive childhood muscle sarcoma with a 5-year survival rate of less than 30%. More than 80% of ARMSs harbor a PAX3-FOXO1 fusion transcription factor. However, expression of PAX3-FOXO1 in muscle cells alone is not sufficient and requires the loss of function of Ink4a/ARF to promote malignant proliferation of muscle cells in vitro or initiate ARMS tumor formation in vivo. This prompted us to examine the signaling pathways required to activate the function of PAX3-FOXO1 and to explore the functional interaction between the Ink4a/ARF and PAX3-FOXO1 signaling pathways. Here we report that inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin (a small molecule selective inhibitor of Cdk4/cyclin D1 that we identified in a screen for compounds that inhibit PAX3-FOXO1) led to inhibition of the transcriptional activity of PAX3-FOXO1 in ARMS cell line Rh30. Consistent with this finding, activation of Cdk4 enhanced the activity of PAX3-FOXO1. In vitro kinase assays revealed that Cdk4 directly phosphorylated PAX3-FOXO1 at Ser430. Whereas fascaplysin did not affect the protein level of PAX3-FOXO1, it did increase the cytoplasmic level of PAX3-FOXO1 in a portion of cells. Our findings indicate that Cdk4 phosphorylates and positively regulates PAX3-FOXO1 and suggest that inhibition of Cdk4 activity should be explored as a promising avenue for developing therapy for ARMS.

The voltage-dependent K+ channels Kv1.3 and Kv1.5 in human cancer

Voltage-dependent K+ channels (Kv) are involved in a number of physiological processes, including immunomodulation, cell volume regulation, apoptosis as well as differentiation. Some Kv channels participate in the proliferation and migration of normal and tumor cells, contributing to metastasis. Altered expression of Kv1.3 and Kv1.5 channels has been found in several types of tumors and cancer cells. In general, while the expression of Kv1.3 apparently exhibits no clear pattern, Kv1.5 is induced in many of the analyzed metastatic tissues. Interestingly, evidence indicates that Kv1.5 channel shows inversed correlation with malignancy in some gliomas and non-Hodgkin's lymphomas. However, Kv1.3 and Kv1.5 are similarly remodeled in some cancers. For instance, expression of Kv1.3 and Kv1.5 correlates with a certain grade of tumorigenicity in muscle sarcomas. Differential remodeling of Kv1.3 and Kv1.5 expression in human cancers may indicate their role in tumor growth and their importance as potential tumor markers. However, despite of this increasing body of information, which considers Kv1.3 and Kv1.5 as emerging tumoral markers, further research must be performed to reach any conclusion. In this review, we summarize what it has been lately documented about Kv1.3 and Kv1.5 channels in human cancer.

The promoter methylation and expression of the O6-methylguanine-DNA methyltransferase gene in uterine sarcoma and carcinosarcoma

O6-methylguanine-DNA methyltransferase (MGMT) gene promoter hypermethylation is observed in a number of solid tumors and is correlated with the silencing of MGMT expression. In glioblastoma patients treated with the alkylating agent temozolomide, MGMT gene methylation status was shown to have predictive value in terms of prolonged overall survival. Recently, temozolomide has demonstrated promising activity in the treatment of soft tissue sarcomas, including those of the uterus. The tissue specimens involving tumor samples and normal uterine fragments were obtained from nine patients with smooth muscle uterine sarcoma, 11 with stromal uterine sarcoma and 17 with mixed uterine tumors. MGMT gene promoter methylation was analyzed by combined bisulfite restriction analysis (COBRA) while its expression levels were assessed using the real-time reverse transcription polymerase chain reaction (qRT-PCR). MGMT promoter methylation was observed in 27% of all tumor samples analyzed. When stratified by the disease type, 55.5% (5/9) of smooth muscle sarcomas, 23.5% (4/17) of mixed uterine tumor tissues and 9% (1/11) of stromal sarcomas showed MGMT methylation. The MGMT promoter methylation was associated with lower levels of gene expression in tumors when compared with those with an unmethylated promoter (P=0.0232) or normal tissues (P=0.0141). To conclude, MGMT promoter methylation and downregulation of gene expression is observed in a fraction of carcinosarcomas and non-epithelial malignant tumors of corpus uteri. The assessment of MGMT promoter methylation status may potentially identify patients who would benefit from temozolomide treatment.

Increased voltage-dependent K+ channel Kv1.3 and Kv1.5 expression correlates with leiomyosarcoma aggressiveness

Voltage-dependent K+ channels (Kv) are involved in the proliferation and differentiation of mammalian cells, since Kv antagonists impair cell cycle progression. Although myofibers are terminally differentiated, some myoblasts may re-enter the cell cycle and proliferate. Since Kv1.3 and Kv1.5 expression is remodeled during tumorigenesis and is involved in smooth muscle proliferation, the purpose of this study was to analyze the expression of Kv1.3 and Kv1.5 in smooth muscle neoplasms. In the present study, we examined human samples of smooth muscle tumors together with healthy specimens. Thus, leiomyoma (LM) and leiomyosarcoma (LMS) tumors were analyzed. Results showed that Kv1.3 was poorly expressed in the healthy muscle and indolent LM specimens, whereas aggressive LMS showed high levels of Kv1.3 expression. Kv1.5 staining was correlated with malignancy. The findings show a remodeling of Kv1.3 and Kv1.5 in human smooth muscle sarcoma. A correlation of Kv1.3 and Kv1.5 expression with tumor aggressiveness was observed. Thus, our results indicate Kv1.5 and Kv1.3 as potential tumorigenic targets for aggressive human LMS.

In Vivo Imaging of Tumor-Propagating Cells, Regional Tumor Heterogeneity, and Dynamic Cell Movements in Embryonal Rhabdomyosarcoma

Embryonal rhabdomyosarcoma (ERMS) is an aggressive pediatric sarcoma of muscle. Here, we show that ERMS-propagating potential is confined to myf5+ cells and can be visualized in live, fluorescent transgenic zebrafish. During early tumor growth, myf5+ ERMS cells reside adjacent normal muscle fibers. By late-stage ERMS, myf5+ cells are reorganized into distinct regions separated from differentiated tumor cells. Time-lapse imaging of late-stage ERMS revealed that myf5+ cells populate newly formed tumor only after seeding by highly migratory myogenin+ ERMS cells. Moreover, myogenin+ ERMS cells can enter the vasculature, whereas myf5+ ERMS-propagating cells do not. Our data suggest that non-tumor-propagating cells likely have important supportive roles in cancer progression and facilitate metastasis.

Abstract 1361: Sarcoma-relevant genetic events identified in a chimeric mouse model of sarcoma in skeletal muscle

Abstract Background. Soft-tissue sarcomas are heterogeneous malignancies of mesodermal, non-hematopoietic origin. Ex-vivo genetic alteration (by activation of Kras(G12V) and deletion of p16INK4A/p19ARF) and intramuscular implantation of discrete mesodermal cell populations, freshly isolated from mouse skeletal muscle, results in the rapid induction of pleomorphic sarcomas. This model system can be utilized as a platform to dissect sarcoma-relevant cellular and genetic events. Methods. The molecular underpinnings of Kras; p16p19null sarcomas were evaluated by whole genome microarray in comparison to normal muscle and to previously published human rhabdomyosarcoma datasets. Upregulation of 141 candidate genes identified by bioinformatic analyses was verified using a customized RT*2 Profiler™ PCR Array (SA Biosciences). The effects of shRNA knockdown of candidate genes on sarcoma growth were evaluated in sarcoma cell lines. Results. Kras; p1619null sarcomas recapitulate gene expression signatures of human rhabdomyosarcomas and identify a conserved cluster of 144 genes that is concordantly upregulated in both mouse and human sarcomas compared to normal skeletal muscle. 74 of these 144 genes have been associated previously with human malignancies, and 28 have been linked specifically to sarcomas. PCR array validation confirmed that 104 of these genes are upregulated in mouse sarcomas compared to normal skeletal muscle, including the BMP antagonist and Shh morphogen Gremlin, previously implicated in human sarcomas (upregulated 1327-fold in mouse sarcomas vs. muscle). Gremlin knockdown in sarcoma cell lines by shRNA results in reduced proliferation, thereby implicating a functional role in sarcoma biology. Conclusions. Our studies identify a small group of genes that are upregulated in sarcomas across species and may be of fundamental importance in sarcomas. Future studies of the genes identified here will likely provide important insights into the events that drive sarcomas in muscle, and identify new targets for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1361. doi:1538-7445.AM2012-1361

Muscle sarcomas and alopecia in A/J mice chronically treated with nicotine

AimsTo evaluate the pathobiologic effects of long-term treatment with nicotine of A/J mice susceptible to tobacco-induced lung carcinogenesis. Main methodsExperimental group of mice received subcutaneous injections of the LD50 dose of (−)nicotine hydrogen tartrate of 3mg/kg/day, 5days per week for 24months, and control group received the vehicle phosphate-buffered saline. Key findingsNicotine treated mice, 78.6%, but none of control of mice, developed neoplasms originating from the uterus or skeletal muscle. Examination of the uterine neoplasms revealed leiomyosarcomas, composed of whorled bundles of smooth-muscle like cells with large and hyperchromatic nuclei. Sections of the thigh neoplasms revealed densely cellular tumors composed of plump spindle cells, with occasional formation of ‘strap’ cells, containing distorted striations. Both neoplasms were positive for desmin staining. A solitary pulmonary adenoma with papillary architecture also occurred in one nicotine treated mouse. Experimental mice also developed transient balding starting as small patches of alopecia that progressed to distinct circumscribed areas of complete hair loss or large areas of diffuse hair loss. SignificanceWe demonstrate for the first time that chronic nicotine treatment can induce the development of muscle sarcomas as well as transient hair loss. These findings may help explain the association of childhood rhabdomyosarcoma with parental smoking and earlier onset of balding in smokers. It remains to be determined whether the pathobiologic effects of nicotine result from its receptor-mediated action and/or its tissue metabolites cotinine and N′-nitrosonornicotine, or toxic effects of reactive oxygen species activated due to possible intracellular accumulation of nicotine.

Differential Expression of Kv1.3 and Kv1.5 Voltage-Dependent K+ Channels in Human Skeletal Muscle Sarcomas

Because Kv1.3 and Kv1.5 K+ channels are remodeled during tumorigenesis and participate in skeletal muscle proliferation, we analyzed their expression in human skeletal muscle sarcomas. Aggressive alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) were studied. Kv1.5 expression was moderate in adult muscle and low in ERMS, whereas it was notable in ARMS and embryonic samples. Kv1.3 expression showed no major differences between RMS and healthy samples. We found a correlation of Kv1.3 and Kv1.5 expression with the tumor malignancy.

Identification of suitable reference genes for gene expression measurement in uterine sarcoma and carcinosarcoma tumors

To date no suitable reference genes have been identified in carcinosarcomas and non-epithelial malignant tumors of corpus uteri for normalizing real-time RT-PCR (qRT-PCR) assays. The purpose of this study was to select appropriate references for gene expression studies in these tumors. We used RNA extracts from 75 tissue samples, representing 50 tumors and 25 fragments of normal uterine tissues obtained from 50 patients treated for mixed tumors, smooth muscle sarcoma and stromal sarcoma of the uterus. qRT-PCR for five potential reference (housekeeping) genes, namely B2M, HMBS, HPRT1, TBP and UBC, was performed. The expression stability of these genes was assayed using geNorm software application. The analysis of gene expression data with geNorm identified HPRT1 as the most stable reference gene, followed by UBC and HMBS, for all the investigated tissues. When stratified by disease, the results still pointed at HPRT1 as the gene that retained the greatest robustness in mixed tumors as well as in smooth muscle and stromal sarcomas. Our work is the first report on reference gene selection for qRT-PCR applications in mixed tumors, smooth muscle sarcoma and stromal sarcoma of the uterus. A ranking of candidate genes' stability values for the three types of tumors is provided and might serve as a valuable guide for future gene expression studies of these rare entities.

Primary renal leiomyosarcoma: A diagnostic challenge

Primary leiomyosarcoma is an extremely rare entity constituting only 0.5–1% of all invasive renal tumors. It is frequently diagnosed on histological examination because it does not have any specific diagnostic features clinically and radiologically. At times, it is difficult to differentiate leiomyosarcoma from the sarcomatoid renal cell carcinoma even in histopathology as both the tumors have spindle-shaped atypical cells. Moreover, some epithelial markers can be present in pure smooth muscle sarcomas, while some smooth muscle markers are positive in carcinomas. Hence, a diagnosis of primary renal leiomyosarcoma should be made with caution. Since the prognosis for a renal sarcoma is particularly poor, differentiation from sarcomatoid renal cell carcinoma is necessary. The diagnostic challenge of one such tumor is discussed.

Modern treatment of gastric gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are rare mesenchymal smooth muscle sarcomas that can arise anywhere within the gastrointestinal tract. Sporadic mutations within the tyrosine kinase receptors of the interstitial cells of Cajal have been identified as the key molecular step in GIST carcinogenesis. Although many patients are asymptomatic, the most common associated symptoms include: abdominal pain, dyspepsia, gastric outlet obstruction, and anorexia. Rarely, GIST can perforate causing life-threatening hemoperitoneum. Most are ultimately diagnosed on cross-sectional imaging studies (i.e., computed tomography and/or magnetic resonance imaging in combination with upper endoscopy. Endoscopic ultrasonographic localization of these tumors within the smooth muscle layer and acquisition of neoplastic spindle cells harboring mutations in the c-KIT gene is pathognomonic. Curative treatment requires a complete gross resection of the tumor. Both open and minimally invasive operations have been shown to reduce recurrence rates and improve long-term survival. While there is considerable debate over whether GIST can be benign neoplasms, we believe that all GIST have malignant potential, but vary in their propensity to recur after resection and metastasize to distant organ sites. Prognostic factors include location, size (i.e., > 5 cm), grade (> 5-10 mitoses per 50 high power fields and specific mutational events that are still being defined. Adjuvant therapy with tyrosine kinase inhibitors, such as imatinib mesylate, has been shown to reduce the risk of recurrence after one year of therapy. Treatment of locally-advanced or borderline resectable gastric GIST with neoadjuvant imatinib has been shown to induce regression in a minority of patients and stabilization in the majority of cases. This treatment strategy potentially reduces the need for more extensive surgical resections and increases the number of patients eligible for curative therapy. The modern surgical treatment of gastric GIST combines the novel use of targeted therapy and aggressive minimally invasive surgical procedures to provide effective treatment for this lethal, but rare gastrointestinal malignancy.

Ewing's sarcoma of the masseter muscle

To present a case of extraskeletal Ewing's sarcoma originating in the masseter muscle, and to review the diagnosis and management of these rare tumours. Case report and literature review. We report a patient with Ewing's sarcoma of the masseter muscle with mandibular invasion. She was treated with induction chemotherapy, salvage surgery and free flap reconstruction. This case highlights the management of these rare tumours. Aggressive multi-modal treatment, including multi-agent chemotherapy, surgical resection and irradiation, appears to offer the best prognosis. Contemporary reconstructive techniques can restore function and form in cases with challenging defects.

Review of Vascular Leiomyosarcoma and Report of a Case Localized to the Greater Saphenous Vein of the Ankle

Smooth muscle sarcomas involving blood vessels, leiomyosarcomas, are rare, making up less than 2% of all leiomyosarcomas. Leiomyosarcoma of the saphenous vein is even more uncommon, with nearly all cases reported occurring in the thigh. This article reviews leiomyosarcoma of blood vessels and reports on a 62-year-old woman with an extremely rare case of a leiomyosarcoma of the distal portion of the greater saphenous at the ankle.

Anti-proliferative effects of GW441756, a novel inhibitor of NGFreceptor tyrosine kinase a (TRKA), in human sarcoma

Several experimental data have shown a relevant involvement of Nerve Growth Factor (NGF) in neoplastic proliferation and survival. NGF acts through two receptors and two distinct transduction pathways: high affinity TrKA receptor connected to proliferation via AKT, and low-affinity p75 receptor connected to apoptosis via caspases. Our previous studies have shown that TrKA inhibitors have a relevant anti-proliferative effects in neoplasia. GW441756 is a novel TrKA-inhibitor (IC50 = 2nM) that displays an higher selectivity on TrKA respect to previous inhibitors and a 100-fold selectivity over a range of other kinases. However, its biological effects in cancer cells is still unknown. The aim of our study was to investigate in vitro the biological effects of this new inhibitor in human muscle sarcoma cancer cell line HTB114, at basal condition and following GW441756 administration. As revealed by thymidine incorporation, GW441756 induced a dose-dependent decrease in neoplastic proliferation. Contemporaneously, Annexin V assay demonstrated a dramatic dose-dependent increase in apoptosis. To further characterize these results, we studied AKT and caspases activation by cytofluorimetric analysis. In agreement to its anti-proliferative-pro-apoptotic effects, GW441756 did not induce AKT activation, but produced a relevant increase of caspase-3 that, in turn, leads to apoptosis. In conclusion, GW441756 has a comparable anti-neoplastic effect respect to previous TrKA inhibitors, but with a lower effective dosage (10 μM vs 50 μM of other TrKAinhibitors). Our data have a preclinical relevance to achieve anti-proliferative effects in muscular sarcomas by TrKA-inhibitors administration.

Granulocytic Sarcoma Involving the Pectoralis Muscle in a Patient with Chronic Myelogenous Leukemia

We report here on a very rare case of granulocytic sarcoma of the pectoralis muscle on the left chest wall of a patient with chronic myelogenous leukemia, and this malady presented as a very rapidly growing hematoma-like mass.

Deficiency in p53 but not Retinoblastoma Induces the Transformation of Mesenchymal Stem Cells In vitro and Initiates Leiomyosarcoma In vivo

Sarcomas have been modeled in mice by the expression of specific fusion genes in mesenchymal stem cells (MSC), supporting the concept that MSCs might be the target initiating cell in sarcoma. In this study, we evaluated the potential oncogenic effects of p53 and/or retinoblastoma (Rb) deficiency in MSC transformation and sarcomagenesis. We derived wild-type, p53(-/-), Rb(-/-), and p53(-/-)Rb(-/-) MSC cultures and fully characterized their in vitro growth properties and in vivo tumorigenesis capabilities. In contrast with wild-type MSCs, Rb(-/-), p53(-/-), and p53(-/-)Rb(-/-) MSCs underwent in vitro transformation and showed severe alterations in culture homeostasis. More importantly, p53(-/-) and p53(-/-)Rb(-/-) MSCs, but not Rb(-/-) MSCs, were capable of tumor development in vivo after injection into immunodeficient mice. p53(-/-) or p53(-/-)Rb(-/-) MSCs originated leiomyosarcoma-like tumors, linking this type of smooth muscle sarcoma to p53 deficiency in fat tissue-derived MSCs. Sca1+ and Sca1 low/- cell populations isolated from ex vivo-established, transformed MSC lines from p53(-/-)Rb(-/-) tumors showed identical sarcomagenesis potential, with 100% tumor penetrance and identical latency, tumor weight, and histologic profile. Our findings define the differential roles of p53 and Rb in MSC transformation and offer proof-of-principle that MSCs could provide useful tools to dissect the sarcoma pathogenesis.