Prognostic Value of CD40 in Adult Soft Tissue Sarcomas

Ottaiano, Alessandro; Chiara, A.; Perrone, Francesco; Botti, Gerardo; Fazioli, Flavio; Rosa, Vincenzo De; Mozzillo, Nicola; Ravo, Vincenzo; Morrica, Brunello; Gallo, Ciro; Pisano, Carmela; Napolitano, Maria; Ascierto, Paolo A.; Iaffaioli, Rosario Vincenzo; Apice, Gaetano

doi:10.1158/1078-0432.ccr-0139-03

Cited by 28 publications

(31 citation statements)

References 46 publications

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“…Much evidence suggests that sarcomas, regardless of subtype, overexpress VEGF (25); VEGF expression was found to correlate with stage, grade, and prognosis (26) and was suggested to play a major role in STS metastatic progression (27). Antiangiogenic therapy provides important potential advantages: a broad spectrum of activity against many STS subtypes; decreased therapeutic resistance as endothelial cells are relatively genetically stable; improved drug access to targets, especially in large, hypoxic STS, in which the tumor per se is not easily accessible; and (hopefully) modest toxicities.…”

Section: Discussionmentioning

confidence: 99%

Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma

Ren

Korchin

Lahat

et al. 2008

Clinical Cancer Research

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Purpose: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment. Experimental Design: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us). Results: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis. Conclusions: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.Available soft tissue sarcoma (STS) chemotherapies have modest response rates with significant toxicities (1). Consequently, new STS therapies must be developed to improve the current STS 5-year survival rates of <50%. However, new STS treatment development and trials validation are hampered by their rarity and remarkable clinical heterogeneity. More than 50 separate STS histologic subtypes are recognized; these possess markedly diverse clinical courses and outcomes, perhaps reflecting the complex and variable array of molecular derangements underlying these STS biological distinctions (2). In the era of targeted therapeutics, exploiting any relevant unifying molecular abnormalities as might exist in STS has appeal. Analogous to solid malignancies, STS consist of both tumor and tumor-associated normal cells; STS growth, migration, and dissemination depend on cross-talk between these two compartments. STS are generally highly vascular and angiogenic, resulting in increased metastatic potential (3). Amidst diversity, these common STS proper...

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Section: Discussionmentioning

confidence: 99%

Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma

Ren

Korchin

Lahat

et al. 2008

Clinical Cancer Research

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“…Ki-67 antigen was first described in 1983 as a nuclear protein associated with cell proliferation (46). Thereafter, high expression of Ki-67 has been correlated with poor prognosis for patients with malignant tumors, including sarcomas (4)(5)(6)(7)(8)(9)(10)(11). Currently, Ki-67 is commonly used as an excellent prognostic marker in soft tissue sarcoma.…”

Section: Discussionmentioning

confidence: 99%

High expression of enhancer of zeste homologue 2 indicates poor prognosis in patients with soft tissue sarcomas

Yamaga

Osaki²,

Kimura³

et al. 2008

Mol Med Rep

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Abstract. Enhancer of zeste homologue 2 (EZH2), a member of the polycomb group of genes, is associated with malignancy in several human cancers. The purpose of this study was to examine the association between EZH2 expression and clinicopathological factors as compared to Ki-67 expression in human soft tissue sarcomas. Expression of EZH2 and Ki-67 was immunohistochemically determined in paraffin-embedded sections from 104 soft tissue sarcomas. High expression of both EZH2 and Ki-67 was significantly correlated with distant metastasis (P<0.01), histologic grade (P<0.01) and poor prognosis (P<0.01), but not with clinicopathological factors such as age, sex, and tumor location and size. Although EZH2 expression was significantly correlated with Ki-67 expression (rs=0.65, P<0.01), multivariate analysis showed that high expression of EZH2, but not of Ki-67, was an independent factor of poor prognosis (relative risk = 2.79; P=0.02). These data suggest that expression of EZH2 is a novel and reliable prognostic marker of human soft tissue sarcomas.

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“…These factors were known to contribute to the prognoses in sarcoma patients (Ottaiano et al, 2005). When the occurrence of distant metastases was used as an endpoint, AFAP1L1 expression was confirmed as a significant factor along with age and FNCLCC grade in univariate analyses (Table 1).…”

Section: Confirmation Of the Significance Of Afap1l1 In Multivariate mentioning

confidence: 91%

Identification of AFAP1L1 as a prognostic marker for spindle cell sarcomas

et al. 2011

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Spindle cell sarcomas consist of tumors with different biological features, of which distant metastasis is the most ominous sign for a poor prognosis. However, metastasis is difficult to predict on the basis of current histopathological analyses. We have identified actin filament-associated protein 1-like 1 (AFAP1L1) as a candidate for a metastasis-predicting marker from the gene expression profiles of 65 spindle cell sarcomas. A multivariate analysis determined that AFAP1L1 was an independent factor for predicting the occurrence of distant metastasis (P ¼ 0.0001), which was further confirmed in another set of 41 tumors by a quantitative mRNA expression analysis. Immunohistochemical staining using paraffin-embedded tumor tissues revealed that the metastasis-free rate was significantly better in tumors negative for AFAP1L1 (P ¼ 0.0093 by log-rank test). Knocking down the AFAP1L1 gene in sarcoma cells resulted in inhibition of the cell invasion, and forced expression of AFAP1L1 in immortalized human mesenchymal stem cells induced anchorage-independent growth and increased cell invasiveness with high activity levels of matrix metallopeptidase. Furthermore, tumor growth in vivo was accelerated in AFAP1L1-transduced sarcoma cell lines. These results suggest that AFAP1L1 has a role in the progression of spindle cell sarcomas and is a prognostic biomarker.

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Prognostic Value of CD40 in Adult Soft Tissue Sarcomas

Abstract: Conclusions: These data suggest that expression of CD40 protein in >50% of cells might indicate an unfavorable prognosis in adult soft tissue sarcomas.

Cited by 28 publications

References 46 publications

Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma

Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma

High expression of enhancer of zeste homologue 2 indicates poor prognosis in patients with soft tissue sarcomas

Identification of AFAP1L1 as a prognostic marker for spindle cell sarcomas

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