Sarcoma Progression Research Articles

Ewing sarcoma inhibition by disruption of EWSR1-FLI1 transcriptional activity and reactivation of p53.

Translocations involving ETS-transcription factors, most commonly leading to the EWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma. Despite knowledge of this driving molecular event, an effective therapeutic strategy is lacking. To test potential treatment regimes, we established a novel Ewing sarcoma zebrafish engraftment model allowing time-effective, dynamic quantification of Ewing sarcoma progression and tumour burden in vivo, applicable for screening of single and combined compounds. In Ewing sarcoma the tumour-suppressor gene TP53 is commonly found to be wild-type, thus providing an attractive target for treatment. Here, we study TP53 wild-type (EW7, CADO-ES1 and TC32) and TP53-deleted (SK-N-MC) Ewing sarcoma cell lines to investigate the potentiating effect of p53 reactivation by Nutlin-3 on treatment with YK-4-279 to block transcriptional activity of EWSR1-FLI1 protein. Blocking EWSR1-FLI1 transcriptional activity reduced Ewing sarcoma tumour cell burden irrespective of TP53 status. We show that simultaneous YK-4-279 treatment with Nutlin-3 to stabilize p53 resulted in an additive inhibition of TP53 wild-type Ewing sarcoma cell burden, whilst not affecting TP53-deleted Ewing sarcoma cells. Improved inhibition of proliferation and migration by combinatorial treatment was confirmed in vivo by zebrafish engraftments. Mechanistically, both compounds together additively induced apoptosis of tumour cells in vivo by engaging distinct pathways. We propose reactivation of the p53 pathway in combination with complementary targeted therapy by EWSR1-FLI1 transcriptional activity disruption as a valuable strategy against p53 wild-type Ewing sarcoma.

Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization.

Sarcomas are mesenchymal tumors showing high molecular heterogeneity, reflected at the histological level by the existence of more than fifty different subtypes. Genetic and epigenetic evidences link aberrant activation of the Wnt signaling to growth and progression of human sarcomas. This phenomenon, mainly accomplished by autocrine loop activity, is sustained by gene amplification, over-expression of Wnt ligands and co-receptors or epigenetic silencing of endogenous Wnt antagonists. We previously showed that pharmacological inhibition of Wnt signaling mediated by Axin stabilization produced in vitro and in vivo antitumor activity in glioblastoma tumors. Here, we report that targeting different sarcoma cell lines with the Wnt inhibitor/Axin stabilizer SEN461 produces a less transformed phenotype, as supported by modulation of anchorage-independent growth in vitro. At the molecular level, SEN461 treatment enhanced the stability of the scaffold protein Axin1, a key negative regulator of the Wnt signaling with tumor suppressor function, resulting in downstream effects coherent with inhibition of canonical Wnt signaling. Genetic phenocopy of small molecule Axin stabilization, through Axin1 over-expression, coherently resulted in strong impairment of soft-agar growth. Importantly, sarcoma growth inhibition through pharmacological Axin stabilization was also observed in a xenograft model in vivo in female CD-1 nude mice. Our findings suggest the usefulness of Wnt inhibitors with Axin stabilization activity as a potentialyl clinical relevant strategy for certain types of sarcomas.

Stereotactic radiosurgery for primary malignant spinal tumors

Objectives:We adopted stereotactic radiosurgery (SRS) to treat primary malignant spinal tumors. The objective of this study was to evaluate local control rate and to identify prognostic factors after SRS for primary malignant spinal tumors.Methods:Medical records and radiological data for 29 patients with primary malignant spinal tumors were retrospectively analyzed. The histological diagnoses were chordoma (11 cases), chondrosarcoma (5 cases), osteosarcoma (3 cases), synovial sarcoma (3 cases), plasmacytoma (2 cases), Ewing sarcoma (2 cases), malignant peripheral nerve sheath tumor (2 cases), and malignant fibrous histiocytoma (1 case). Patient age ranged from 11 to 68 years (median, 46 years). Surgical resection and percutaneous biopsy were chosen as initial treatments in 25 and 4 cases, respectively. Stereotactic radiosurgery was used as primary treatment method in 14 cases and as a salvage treatment for progressed lesions in 15 cases. Distant metastasis was noted in two sarcoma patients. Eleven patients had undergone previous conventional external beam radiation therapy (cEBRT) before SRS. Overall survival, local progression-free survival, and the prognostic factors affecting local recurrence were investigated.Results:Tumor volume ranged from 2·0 to 235 cc (median, 14 cc). Delivered radiation doses were from 12 to 50 Gy with two to six sessions. The mean radiation dose converted into a biological effective dose (BED) was 60 Gy (range, 43–105 Gy). The mean follow-up period was 50 months (range, 8–126 months). The mean overall survival was 84 months for chordoma patients and 104 months for sarcoma patients. No factors that affected overall survival were found. The mean local progression-free survival was 56 months for chordoma patients and 73 months for sarcoma patients. The recurrent mode of presentation was predictive of local progression of spinal sarcomas (P = 0·009). However, in chordoma patients, no factors were found to correlate with local recurrence.Conclusion:These preliminary results suggest that SRS could provide good local control when applied as postoperative adjuvant or salvage treatment after cEBRT for primary malignant spinal tumors.

MiR‐125b inhibits cell biological progression of Ewing's sarcoma by suppressing the PI3K/Akt signalling pathway

Increasing evidence has suggested the close relationship between microRNAs (miRNAs) dysregulation and the carcinogenesis of Ewing's sarcoma (ES), among of which miR-125b has been reported to be decreased in ES tissues recently. Strikingly, ectopic expression of miR-125b could suppress cell proliferation of ES cell line A673, suggesting the tumor suppressor role of miR-125b in ES. However, the other accurate mechanistic functions and relative molecule mechanisms are largely unknown. Herein, we completed a series of experiments to investigate the role of miR-125b in Ewing's sarcoma. We restored the expression of miR-125b in ES cell line A673 through transfection with miR-125b mimics. To further understand the role of miR-125b in ES, we detected the effects of miR-125b on the cell proliferation, migration and invasion, cell cycle as well as cell apoptosis. We found that restored expression of miR-125b in ES cell line A673 inhibited cell proliferation, migration and invasion, arrested cell cycle progression, and induced cell apoptosis. Moreover, bioinformatic prediction suggested the oncogene, phosphoinositide-3-kinase catalytic subunit delta (PIK3CD), was a target gene of miR-125b in ES cells. Further quantitative RT-PCR and western blot assays identified over-expression of miR-125b suppressed the expression of PIK3CD mRNA and protein. PIK3CD participates in regulating the PI3K signaling pathway, which has been reported to play an important role in the development of ES. Suppression of PIK3CD down-regulated the expression of phospho-AKT and phospho-mTOR proteins and inhibited the biologic progression of A673 cells. Collectively, these data suggest that miR-125b functions as a tumor suppressor by targeting the PI3K/Akt/mTOR signaling pathway, and may provide potential therapy strategy for ES patients by targeting miRNA expression.

Identification of Three Molecular and Functional Subtypes in Canine Hemangiosarcoma through Gene Expression Profiling and Progenitor Cell Characterization

Canine hemangiosarcomas have been ascribed to an endothelial origin based on histologic appearance; however, recent findings suggest that these tumors may arise instead from hematopoietic progenitor cells. To clarify this ontogenetic dilemma, we used genome-wide expression profiling of primary hemangiosarcomas and identified three distinct tumor subtypes associated with angiogenesis (group 1), inflammation (group 2), and adipogenesis (group 3). Based on these findings, we hypothesized that a common progenitor may differentiate into the three tumor subtypes observed in our gene profiling experiment. To investigate this possibility, we cultured hemangiosarcoma cell lines under normal and sphere-forming culture conditions to enrich for tumor cell progenitors. Cells from sphere-forming cultures displayed a robust self-renewal capacity and exhibited genotypic, phenotypic, and functional properties consistent with each of the three molecular subtypes seen in primary tumors, including expression of endothelial progenitor cell (CD133 and CD34) and endothelial cell (CD105, CD146, and αvβ3 integrin) markers, expression of early hematopoietic (CD133, CD117, and CD34) and myeloid (CD115 and CD14) differentiation markers in parallel with increased phagocytic capacity, and acquisition of adipogenic potential. Collectively, these results suggest that canine hemangiosarcomas arise from multipotent progenitors that differentiate into distinct subtypes. Improved understanding of the mechanisms that determine the molecular and phenotypic differentiation of tumor cells in vivo could change paradigms regarding the origin and progression of endothelial sarcomas.

Role of Inflammation-Associated Microenvironment in Tumorigenesis and Metastasis

The tumor microenvironment contributes to every aspect of carcinogenesis and therefore offers promising targets for cancer therapy. Compared to chemotherapy alone, targeting tumor cells as well as key components of the tumor microenvironment significantly improve the clinical outcomes of patients. A better understanding of the interaction between tumor cells and the microenvironment could provide new therapeutic options and accelerate the development of novel anti-cancer drugs. In this review, we first defined the tumor microenvironment and then discussed the role of the tumor microenvironment in the initiation and progression of cancer focusing on three major pathways in a tumor cell life cycle: 1) growth and intravasation; in this section, the epithelial-mesenchymal transition (EMT), tumor cell migration, and tumor angiogenesis are reviewed. 2) dissemination; the activation and aggregation of platelets, as an important feature for the survival of tumor cells in the circulation, are reviewed under this section. 3) arrest, extravasation and growth at the secondary sites; the main contents of this section include tissue tropism in metastasis, the formation of the pre-metastatic niche, tumor cell adhesion and extravasation, the mesenchymal to epithelial transition (MET), and the formation of micrometastases and macrometastases. Finally, we briefly introduce the drug resistance mediated by the tumor microenvironment, and also summarize potential drug targets based on the current knowledge of the tumor microenvironment. Although the tumor microenvironment is equally important in the progression of carcinomas, leukemias, and sarcomas, in this review we focus on the common form of malignancy, carcinomas, which represent the malignancy derived from the epithelia.

Correlation of Oncologic Long-Term Results and Genetic Instability in Soft Tissue Sarcomas

Purpose: Soft tissue sarcomas (STS) represent a heterotop group of tumours. Microsatellite instabilities (MSI) and loss of heterozygosity (LOH) as phenomena of a genetic instability should be analysed in STS and correlated with the long-term oncologic outcome. Methods: Patients treated for a STS with a follow-up of at least 10 years were included. Thus, 86 patients (mean age 50.5 years, range 16-86 years) treated for a STS between 1993 and 2000 were routinely controlled every 6 months. Incidence of local recurrences, distant metastases, and overall survival were analysed. Sixty-six tumour samples were available for microsatellite analysis using the former traditional method of PCR amplification at 6 loci in the neighbourhood of hMSH2, hMLH1, p53, p16, rb1, and hTR. Results: There were 30 low-grade and 56 high-grade sarcomas. The mean follow-up was 144 months (120-192 months). Twenty-nine patients died of their disease. Local recurrences were seen in 13 patients, whereas metastases were noticed in 23 patients. The overall survival was dependent on the tumour stage (p<0.05), whereas the local tumour control (incidence of local recurrence) was influenced by the surgical margin achieved (p<0.05). The molecular biologic findings revealed 67% of the investigated loci as informative. MSI was found in 6.8% of the informative loci, whereas LOH in 18.8%, respectively. LOH was present in high-grade tumours in 23.8%, whereas in 1.7% in low-grade tumours. In high-grade sarcomas, the 5-year and 10-year survival probabilities were significantly lower in LOH-positive tumours (48.6% and 38%) than in LOH-negative tumours (72.5% and 62%). Conclusion: The overall survival in soft tissue sarcoma is mainly influenced by the tumour stage. In high-grade sarcomas, the survival rate will drop even after 5 years. The detection of loss of heterozygosity represents a negative prognostic predictor in high-grade sarcomas. Microsatellite instability is a rare phenomenon supposing no relevance in the oncogenesis and tumour progression of soft tissue sarcomas.

The role of the CXCL12-CXCR4/CXCR7 axis in the progression and metastasis of bone sarcomas (Review)

Bone sarcomas, which comprise less than 1% of all human malignancies, are a group of relatively rare mesenchymal-derived tumors. They are mainly composed of osteosarcoma, chondrosarcoma and Ewing's sarcoma. In spite of advances in adjuvant chemotherapy and wide surgical resection, prognosis remains poor due to the high propensity for lung metastasis, which is the leading cause of mortality in patients with bone sarcomas. Chemokines are a superfamily of small pro-inflammatory chemoattractant cytokines which can bind to specific Gprotein-coupled seven-span transmembrane receptors. Chemokine12 (CXCL12), also designated as stromal cell-derived factor-1 (SDF-1), is able to bind to its cognate receptors, chemokine receptor4 (CXCR4) andchemokine receptor7 (CXCR7), with high affinity. The binding of CXCL12 to CXCR4/CXCR7 stimulates the activation of several downstream signaling pathways that regulate tumor progression and metastasis. In this review, the structure and function of CXCL12 and its receptors, CXCR4 and CXCR7, as well as many factors affecting their expression are discussed. Phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways are the two most important downstream pathways regulated by the CXCL12-CXCR4/CXCR7 interaction. CXCR4 expression in bone sarcomas, including tumor cells and samples and the correlation between CXCR4/CXCR7 expression and the survival of patients with bone sarcomas are also discussed. In addition, we review the involvement of the CXCL12‑CXCR4/CXCR7 axis in the growth and metastasis of bone sarcomas and the targeting of this axis in preclinical studies.

Hypoxia Signaling—License to Metastasize

Hypoxia-inducible factors (HIF) have long been linked to malignant tumor phenotypes in various cancer types, and several downstream mediators of HIF action are deregulated in metastatic carcinomas. A new study links hypoxia-induced collagen remodeling to sarcoma progression, providing evidence for unifying mechanisms of carcinoma and sarcoma metastasis.

Expression of SIRT1 and DBC1 Is Associated with Poor Prognosis of Soft Tissue Sarcomas

Recently, the roles of SIRT1 and deleted in breast cancer 1 (DBC1) in human cancer have been extensively studied and it has been demonstrated that they are involved in many human carcinomas. However, their clinical significance for soft-tissue sarcomas has not been examined. In this study, we evaluated the expression and prognostic significance of the expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 in 104 cases of soft-tissue sarcomas. RESULTS: Immunohistochemical expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were seen in 71%, 74%, 53%, 48%, and 73% of sarcomas, respectively. The expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were significantly correlated with advanced clinicopathological parameters such as higher clinical stage, higher histological grade, increased mitotic counts, and distant metastasis. The expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 were significantly correlated with each other and positive expression of all of these predicted shorter overall survival and event-free survival by univariate analysis. Multivariate analysis revealed the expression of SIRT1 as an independent prognostic indicator for overall survival and event-free survival of sarcoma patients. In conclusion, this study demonstrates that SIRT1- and DBC1-related pathways may be involved in the progression of soft-tissue sarcomas and can be used as clinically significant prognostic indicators for sarcoma patients. Moreover, the SIRT1- and DBC1-related pathways could be new therapeutic targets for the treatment of sarcomas.

Irreversible Hepatotoxicity After Administration of Trabectedin to a Pleiomorphic Sarcoma Patient with a Rare ABCC2 Polymorphism: A Case Report

We describe here the case of a 60-year old male patient treated for an extensive local progression of a pleiomorphic sarcoma on the right tibial crest with second-line trabectedin. Two cycles were administrated before a major liver toxicity was retrieved, with both cytolytic and cholestatic hepatitis quickly associated with irreversible jaundice. The radiological, histological, chemistry and pharmacogenetic investigations led us to diagnose chronic hepatobiliary toxicity with portal fibrosis, cholangiolitis damages and chronic hepatopathy. The patient had a deficient variant genotype of ABCC2 (c.-24TT, c.4488CT and c.4544GA), which has been suggested to play a role in excretion of toxic metabolites of trabectedin. This case report is, to our knowledge, the first description of trabectedin's irreversible liver toxicity in a human patient. Supported by a thorough review of the literature, this hepatitis is thought to have resulted from a multihit process involving genetic variants of ABC proteins and comedication.

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

The Akt/mammalian target of rapamycin (mTOR) pathway, downstream from phosphatidylinositol 3-kinase (PI3K), mediates cell survival and proliferation. Although this pathway reportedly contributes to the progression of synovial sarcoma, its prognostic impact has not been clarified. The authors analyzed clinicopathologic data and phosphorylation status of Akt (a serine/threonine kinase also known as protein kinase B), mTOR, the eukaryotic translation initiation factor 4E binding protein (4E-BP1), and the S6 ribosomal protein by immunohistochemical analysis of 120 formalin-fixed, paraffin-embedded samples and by Western blot analysis of 24 frozen samples from 112 patients with synovial sarcoma. Akt, mTOR, 4E-BP1, and S6 were activated in 76.5%, 67.6%, 59.6%, and 42.6% of samples, respectively. Immunohistochemically positive phosphorylated (p) mTOR (pmTOR) and p4E-BP1 results were correlated with higher mitotic activity, and positive p4E-BP1 results were correlated with greater necrosis. No mutations around the hot spots in the PI3K catalytic subunit α (PI3KCA) and Akt1 genes were observed. In multivariate analysis of clinicopathologic parameters, frequent mitosis was a risk factor for shorter overall survival; and male sex, visceral location, larger tumor size, and frequent mitosis were identified as risk factors for shorter event-free survival. Positive pmTOR and p4E-BP1 results were correlated significantly with shorter overall survival, and positive p4E-BP1 results were correlated with shorter event-free survival in univariate analysis. Positive pAkt results were associated significantly with shorter event-free survival in multivariate analysis. In this study, the Akt/mTOR pathway was activated and was associated with worse clinical and pathologic behavior in patients with synovial sarcoma. The authors propose that this pathway may have potential as a therapeutic target.

Towards a better understanding of Kaposi sarcoma-associated immune reconstitution inflammatory syndrome

Towards a better understanding of Kaposi sarcoma-associated immune reconstitution inflammatory syndrome

Effect of loco regional anaesthesia on tumor progression of sarcomas: a retrospective study

Effect of loco regional anaesthesia on tumor progression of sarcomas: a retrospective study

Dual Pten/Tp53 Suppression Promotes Sarcoma Progression by Activating Notch Signaling

Soft tissue sarcomas are a heterogeneous group of tumors associated with poor clinical outcome. Although a subset of soft tissue sarcomas is characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and Tp53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas, leiomyosarcomas, and carcinosarcomas that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient, whereas the wild-type allele of Tp53 invariably gained point mutations. Gene expression profiles showed up-regulated Notch signaling in Pten(Δ/+)Tp53(Δ/+) tumors compared with Pten(+/+)Tp53(Δ/+) tumors. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of Tp53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells and activated the Notch pathway. Moreover, the increased oncogenic behavior of Pten(Δ/+)Tp53(Δ/+) and shPten-transduced Pten(+/+)Tp53(Δ/+) tumor cells was counteracted by treatment with a γ-secretase inhibitor, suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and Tp53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the cross talk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying patients with high-gradesarcoma for targeted treatments.

Elucidating potentially significant genomic regions involved in the initiation and progression of undifferentiated pleomorphic sarcoma

Sarcomas are cancers that arise in soft tissues or bone and make up a small percentage of malignancies. In an effort to identify potential genetic targets for therapy, this study explores the genomic landscape of a metastatic undifferentiated pleomorphic sarcoma (UPS) with spindle cell morphology. Thick sections (50 µm) of formalin-fixed, paraffin-embedded tissue from a primary, recurrent, and metastatic tumor were collected and processed from a single patient for DNA content-based flow-sorting and analyses. Nuclei of diploid and aneuploid populations were sorted from the malignant tissues and their genomes interrogated with array comparative genomic hybridization. The third sample was highly degraded and did not contain any intact ploidy peaks in our flow assays. A 2.5N aneuploid population was identified in the primary and recurrent sample. We detected a series of shared and unique genomic aberrations in the sorted aneuploid populations. The patterns of aberrations suggest that two similar but independent clonal populations arose during the clinical history of this rare tumor. None of these aberrations were detected in the matching sorted diploid samples. The targeted regions of interest might play a role in UPS and may lead to clinical significance with further investigation.

NG2/CSPG4-collagen type VI interplays putatively involved in the microenvironmental control of tumour engraftment and local expansion

In soft-tissue sarcoma patients, enhanced expression of NG2/CSPG4 proteoglycan in pre-surgical primary tumours predicts post-surgical metastasis formation and thereby stratifies patients into disease-free survivors and patients destined to succumb to the disease. Both primary and secondary sarcoma lesions also up-regulate collagen type VI, a putative extracellular matrix ligand of NG2, and this matrix alteration potentiates the prognostic impact of NG2. Enhanced constitutive levels of the proteoglycan in isolated sarcoma cells closely correlate with a superior engraftment capability and local growth in xenogenic settings. This apparent NG2-associated malignancy was also corroborated by the diverse tumorigenic behaviour in vitro and in vivo of immunoselected NG2-expressing and NG2-deficient cell subsets, by RNAi-mediated knock down of endogenous NG2, and by ectopic transduction of full-length or deletion constructs of NG2. Cells with modified expression of NG2 diverged in their interaction with purified Col VI, matrices supplemented with Col VI, and cell-free matrices isolated from wild-type and Col VI null fibroblasts. The combined use of dominant-negative NG2 mutant cells and purified domain fragments of the collagen allowed us to pinpoint the reciprocal binding sites within the two molecules and to assert the importance of this molecular interaction in the control of sarcoma cell adhesion and motility. The NG2-mediated binding to Col VI triggered activation of convergent cell survival- and cell adhesion/migration-promoting signal transduction pathways, implicating PI-3K as a common denominator. Thus, the findings point to an NG2-Col VI interplay as putatively involved in the regulation of the cancer cell-host microenvironment interactions sustaining sarcoma progression.

Distinct Effects of Ligand-Induced PDGFRα and PDGFRβ Signaling in the Human Rhabdomyosarcoma Tumor Cell and Stroma Cell Compartments

Platelet-derived growth factor receptors (PDGFR) α and β have been suggested as potential targets for treatment of rhabdomyosarcoma, the most common soft tissue sarcoma in children. This study identifies biologic activities linked to PDGF signaling in rhabdomyosarcoma models and human sample collections. Analysis of gene expression profiles of 101 primary human rhabdomyosarcomas revealed elevated PDGF-C and -D expression in all subtypes, with PDGF-D as the solely overexpressed PDGFRβ ligand. By immunohistochemistry, PDGF-CC, PDGF-DD, and PDGFRα were found in tumor cells, whereas PDGFRβ was primarily detected in vascular stroma. These results are concordant with the biologic processes and pathways identified by data mining. While PDGF-CC/PDGFRα signaling associated with genes involved in the reactivation of developmental programs, PDGF-DD/PDGFRβ signaling related to wound healing and leukocyte differentiation. Clinicopathologic correlations further identified associations between PDGFRβ in vascular stroma and the alveolar subtype and with presence of metastases. Functional validation of our findings was carried out in molecularly distinct model systems, where therapeutic targeting reduced tumor burden in a PDGFR-dependent manner with effects on cell proliferation, vessel density, and macrophage infiltration. The PDGFR-selective inhibitor CP-673,451 regulated cell proliferation through mechanisms involving reduced phosphorylation of GSK-3α and GSK-3β. Additional tissue culture studies showed a PDGFR-dependent regulation of rhabdosphere formation/cancer cell stemness, differentiation, senescence, and apoptosis. In summary, the study shows a clinically relevant distinction in PDGF signaling in human rhabdomyosarcoma and also suggests continued exploration of the influence of stromal PDGFRs on sarcoma progression.

Gene Expression Profiling Associated with the Progression of Classic Kaposi's Sarcoma

Although Kaposi's sarcoma (KS) gene expression profile is closer to lymphatic (LEC) rather than blood vascular endothelial cells (BEC), uncertainty still surrounds the cellular origin of KS. To follow KS progression from early to late (nodular) stage, and characterize the molecular fingerprinting associated with each stage, gene arrays were used to compare gene expression profile of 9 skin samples of classic KS (4 Early, 2 Mixed, and 3 Nodular CKS samples) to 4 normal samples. Results for selected genes were validated by Real-time (RT) PCR and immunohistochemistry. Genes regulating immune and defense responses, angiogenesis, apoptosis and proliferation were differentially expressed in different KS stages compared to normal skin. Hierarchical clustering separated normal skin from KS with a clear gradient from early to nodular KS lesions. The gene expression level of endothelium markers, metalloproteinases, angiogenic factors and chemokines, gradually increased from normal through all KS stages. The expression of LEC genes highly increased from early to nodular KS. In the initiation phase we noticed a higher expression of growth factors, as compared to progressive stages. LEC and BEC markers co-exist in “KS expression signature”, although the LEC signature prevailed. Our results also show a complex environment of inflammatory cells and chemokines during KS evolution. A pathogenic hypothesis where cellular hyperproliferation is driven by local expression of chemokines and growth factors without clonal expansion of cells is suggested.

Malignant Transformation of Mastocytoma Developed on Skin Mastocytosis Into Cutaneous Mast Cell Sarcoma

Mastocytosis is a group of disorders characterized by abnormal mast cell proliferation, involving the skin in 80% of cases. Cutaneous mastocytosis, which appears in childhood in 60% of cases, usually has a benign course with a gradually regressive evolution before puberty. Mast cell sarcomas, part of the systemic forms of mastocytosis, are very rare tumors characterized by a destructive growth of highly atypical mast cells, with secondary spread, poor prognosis, and low survival rates. We report the first known case of primary cutaneous mast cell sarcoma due to the transformation of a benign solitary mastocytoma in an adult suffering from an unregressive localized cutaneous mastocytosis. Histologic characteristics of the tumor, mutation analysis, and c-Kit expression were compared with available data. Wide surgical excision of the tumor followed by adjuvant local radiotherapy were performed, and for the first time the use of imatinib was attempted, as neoplastic mast cells expressed the CD117 marker. However, they failed to control the progression of sarcoma. To date, no treatment is known to be effective for this disease, which is associated with short-term survival of the patients.