International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Sarcoma: Molecular Pathology, Diagnostics, and Therapeutics

by Shinji Miwa, Norio Yamamoto and Hiroyuki Tsuchiya

Int. J. Mol. Sci. 2023, 24(6), 5833; https://doi.org/10.3390/ijms24065833 - 19 Mar 2023

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Abstract

Although the incidence of sarcomas accounts for less than 1% of all malignancies, they are classified into more than 50 different subtypes with different biological behaviours [...] Full article

(This article belongs to the Special Issue Sarcoma)

Research

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19 pages, 3195 KiB

Open AccessArticle

Efficacy of Eribulin Plus Gemcitabine Combination in L-Sarcomas

by María López-Álvarez, Cristina González-Aguilera, David S. Moura, Paloma Sánchez-Bustos, José L. Mondaza-Hernández, Marta Martín-Ruiz, Marta Renshaw, Rafael Ramos, Carolina Castilla, Elena Blanco-Alcaina, Nadia Hindi and Javier Martín-Broto

Int. J. Mol. Sci. 2023, 24(1), 680; https://doi.org/10.3390/ijms24010680 - 30 Dec 2022

Cited by 2 | Viewed by 1899

Abstract

Although the overall survival of advanced soft-tissue sarcoma (STS) patients has increased in recent years, the median progression-free survival is lower than 5 months, meaning that there is an unmet need in this population. Among second-line treatments for advanced STS, eribulin is an [...] Read more.

Although the overall survival of advanced soft-tissue sarcoma (STS) patients has increased in recent years, the median progression-free survival is lower than 5 months, meaning that there is an unmet need in this population. Among second-line treatments for advanced STS, eribulin is an anti-microtubule agent that has been approved for liposarcoma. Here, we tested the combination of eribulin with gemcitabine in preclinical models of L-sarcoma. The effect in cell viability was measured by MTS and clonogenic assay. Cell cycle profiling was studied by flow cytometry, while apoptosis was measured by flow cytometry and Western blotting. The activity of eribulin plus gemcitabine was evaluated in in vivo patient-derived xenograft (PDX) models. In L-sarcoma cell lines, eribulin plus gemcitabine showed to be synergistic, increasing the number of hypodiploid events (increased subG1 population) and the accumulation of DNA damage. In in vivo PDX models of L-sarcomas, eribulin combined with gemcitabine was a viable scheme, delaying tumour growth after one cycle of treatment, being more effective in leiomyosarcoma. The combination of eribulin and gemcitabine was synergistic in L-sarcoma cultures and it showed to be active in in vivo studies. This combination deserves further exploration in the clinical context. Full article

(This article belongs to the Special Issue Sarcoma)

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14 pages, 2021 KiB

Open AccessArticle

The Efficacy of Molecular Analysis in the Diagnosis of Bone and Soft Tissue Sarcoma: A 15-Year Mono-Institutional Study

by Stefania Benini, Gabriella Gamberi, Stefania Cocchi, Giovanna Magagnoli, Angela Rosa Fortunato, Enrica Sciulli, Alberto Righi and Marco Gambarotti

Int. J. Mol. Sci. 2023, 24(1), 632; https://doi.org/10.3390/ijms24010632 - 30 Dec 2022

Cited by 2 | Viewed by 1380

Abstract

The histological diagnosis of sarcoma can be difficult as it sometimes requires the combination of morphological and immunophenotypic analyses with molecular tests. A total of 2705 tissue samples of sarcoma consecutively collected from 2006 until 2020 that had undergone molecular analysis were assessed [...] Read more.

The histological diagnosis of sarcoma can be difficult as it sometimes requires the combination of morphological and immunophenotypic analyses with molecular tests. A total of 2705 tissue samples of sarcoma consecutively collected from 2006 until 2020 that had undergone molecular analysis were assessed to evaluate their diagnostic utility compared with histological assessments. A total of 3051 molecular analyses were performed, including 1484 gene fusions tested by c/qRT–PCR, 992 gene rearrangements analysed by FISH, 433 analyses of the gene status of MDM2, 126 mutational analyses and 16 NGS analysis. Of the samples analysed, 68% were from formalin-fixed, paraffin-embedded tissue and 32% were from frozen tissue. C/qRT–PCR and FISH analyses were conclusive on formalin-fixed, paraffin-embedded tissue in 74% and 76% of samples, respectively, but the combination of the two methods gave us conclusive results in 96% and 89% of frozen and formalin-fixed, paraffin-embedded tissues, respectively. We demonstrate the utility of c/qRT–PCR and FISH for sarcoma diagnosis and that each has advantages in specific contexts. We conclude that it is possible to accurately predict the sarcoma subtype using a panel of different subtype-specific FISH probes and c/qRT–PCR assays, thereby greatly facilitating the differential diagnosis of these tumours. Full article

(This article belongs to the Special Issue Sarcoma)

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16 pages, 1814 KiB

Open AccessArticle

Neurofibromin Deficiency Causes Epidermal Growth Factor Receptor Upregulation through the Activation of Ras/ERK/SP1 Signaling Pathway in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheet Tumor

by Gun-Hoo Park, Su-Jin Lee, Chang-Gun Lee, Jeonghyun Kim, Eunkuk Park and Seon-Yong Jeong

Int. J. Mol. Sci. 2021, 22(24), 13308; https://doi.org/10.3390/ijms222413308 - 10 Dec 2021

Cited by 1 | Viewed by 3047

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant human genetic disorder. The progression of benign plexiform neurofibromas to malignant peripheral nerve sheet tumors (MPNSTs) is a major cause of mortality in patients with NF1. Although elevated epidermal growth factor receptor (EGFR) expression plays [...] Read more.

Neurofibromatosis type 1 (NF1) is an autosomal dominant human genetic disorder. The progression of benign plexiform neurofibromas to malignant peripheral nerve sheet tumors (MPNSTs) is a major cause of mortality in patients with NF1. Although elevated epidermal growth factor receptor (EGFR) expression plays a crucial role in the pathogenesis of MPNST, the cause of EGFR overexpression remains unclear. Here, we assessed EGFR expression levels in MPNST tissues of NF1 patients and NF1 patient-derived MPNST cells. We found that the expression of EGFR was upregulated in MPNST tissues and MPNST cells, while the expression of neurofibromin was significantly decreased. Manipulation of NF1 expression by NF1 siRNA treatment or NF1-GAP-related domain overexpression demonstrated that EGFR expression levels were closely and inversely correlated with neurofibromin levels. Notably, knockdown of the NF1 gene by siRNA treatment augmented the nuclear localization of phosphorylated SP1 (pSP1) and enhanced pSP1 binding to the EGFR gene promoter region. Our results suggest that neurofibromin deficiency in NF1-associated MPNSTs enhances the Ras/ERK/SP1 signaling pathway, which in turn may lead to the upregulation of EGFR expression. This study provides insight into the progression of benign tumors and novel therapeutic approaches for treatment of NF1-associated MPNSTs. Full article

(This article belongs to the Special Issue Sarcoma)

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23 pages, 5498 KiB

Open AccessArticle

MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells

by Matteo Cassandri, Silvia Pomella, Alessandra Rossetti, Francesco Petragnano, Luisa Milazzo, Francesca Vulcano, Simona Camero, Silvia Codenotti, Francesca Cicchetti, Roberto Maggio, Claudio Festuccia, Giovanni Luca Gravina, Alessandro Fanzani, Francesca Megiorni, Marialuigia Catanoso, Cinzia Marchese, Vincenzo Tombolini, Franco Locatelli, Rossella Rota and Francesco Marampon

Int. J. Mol. Sci. 2021, 22(19), 10671; https://doi.org/10.3390/ijms221910671 - 1 Oct 2021

Cited by 14 | Viewed by 3166

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often [...] Read more.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS. Full article

(This article belongs to the Special Issue Sarcoma)

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10 pages, 2210 KiB

Open AccessArticle

RABL6A Regulates Schwann Cell Senescence in an RB1-Dependent Manner

by Jordan L. Kohlmeyer, Courtney A. Kaemmer, Shaikamjad Umesalma, Francoise A. Gourronc, Aloysius J. Klingelhutz and Dawn E. Quelle

Int. J. Mol. Sci. 2021, 22(10), 5367; https://doi.org/10.3390/ijms22105367 - 20 May 2021

Cited by 7 | Viewed by 2417

Abstract

Schwann cells are normally quiescent, myelinating glia cells of the peripheral nervous system. Their aberrant proliferation and transformation underlie the development of benign tumors (neurofibromas) as well as deadly malignant peripheral nerve sheath tumors (MPNSTs). We discovered a new driver of MPNSTs, an [...] Read more.

Schwann cells are normally quiescent, myelinating glia cells of the peripheral nervous system. Their aberrant proliferation and transformation underlie the development of benign tumors (neurofibromas) as well as deadly malignant peripheral nerve sheath tumors (MPNSTs). We discovered a new driver of MPNSTs, an oncogenic GTPase named RABL6A, that functions in part by inhibiting the RB1 tumor suppressor. RB1 is a key mediator of cellular senescence, a permanent withdrawal from the cell cycle that protects against cell immortalization and transformation. Based on the RABL6A-RB1 link in MPNSTs, we explored the hypothesis that RABL6A promotes Schwann cell proliferation and abrogates their senescence by inhibiting RB1. Using sequentially passaged normal human Schwann cells (NHSCs), we found that the induction of replicative senescence was associated with reduced expression of endogenous RABL6A. Silencing RABL6A in low passage NHSCs caused premature stress-induced senescence, which was largely rescued by co-depletion of RB1. Consistent with those findings, Rabl6-deficient MEFs displayed impaired proliferation and accelerated senescence compared to wildtype MEFs. These results demonstrate that RABL6A is required for maintenance of proper Schwann cell proliferation and imply that aberrantly high RABL6A expression may facilitate malignant transformation. Full article

(This article belongs to the Special Issue Sarcoma)

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Review

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12 pages, 1071 KiB

Open AccessReview

Towards the Search for Potential Biomarkers in Osteosarcoma: State-of-the-Art and Translational Expectations

by Leonel Pekarek, Basilio De la Torre-Escuredo, Oscar Fraile-Martinez, Cielo García-Montero, Miguel A. Saez, David Cobo-Prieto, Luis G. Guijarro, Jose V. Saz, Patricia De Castro-Martinez, Diego Torres-Carranza, Tatiana Pekarek, Ana Clara Carrera, Melchor Alvarez-Mon and Miguel A. Ortega

Int. J. Mol. Sci. 2022, 23(23), 14939; https://doi.org/10.3390/ijms232314939 - 29 Nov 2022

Cited by 9 | Viewed by 1878

Abstract

Osteosarcoma represents a rare cause of cancer in the general population, accounting for <1% of malignant neoplasms globally. Nonetheless, it represents the main cause of malignant bone neoplasm in children, adolescents and young adults under 20 years of age. It also presents another [...] Read more.

Osteosarcoma represents a rare cause of cancer in the general population, accounting for <1% of malignant neoplasms globally. Nonetheless, it represents the main cause of malignant bone neoplasm in children, adolescents and young adults under 20 years of age. It also presents another peak of incidence in people over 50 years of age and is associated with rheumatic diseases. Numerous environmental risk factors, such as bone diseases, genetics and a history of previous neoplasms, have been widely described in the literature, which allows monitoring a certain group of patients. Diagnosis requires numerous imaging tests that make it possible to stratify both the local involvement of the disease and its distant spread, which ominously determines the prognosis. Thanks to various clinical trials, the usefulness of different chemotherapy regimens, radiotherapy and surgical techniques with radical intent has now been demonstrated; these represent improvements in both prognosis and therapeutic approaches. Osteosarcoma patients should be evaluated in reference centres by multidisciplinary committees with extensive experience in proper management. Although numerous genetic and rheumatological diseases and risk factors have been described, the use of serological, genetic or other biomarkers has been limited in clinical practice compared to other neoplasms. This limits both the initial follow-up of these patients and screening in populations at risk. In addition, we cannot forget that the diagnosis is mainly based on the direct biopsy of the lesion and imaging tests, which illustrates the need to study new diagnostic alternatives. Therefore, the purpose of this study is to review the natural history of the disease and describe the main biomarkers, explaining their clinical uses, prognosis and limitations. Full article

(This article belongs to the Special Issue Sarcoma)

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24 pages, 1193 KiB

Open AccessReview

Translational Implications for Radiosensitizing Strategies in Rhabdomyosarcoma

by Silvia Pomella, Antonella Porrazzo, Matteo Cassandri, Simona Camero, Silvia Codenotti, Luisa Milazzo, Francesca Vulcano, Giovanni Barillari, Giovanni Cenci, Cinzia Marchese, Alessandro Fanzani, Francesca Megiorni, Rossella Rota and Francesco Marampon

Int. J. Mol. Sci. 2022, 23(21), 13281; https://doi.org/10.3390/ijms232113281 - 31 Oct 2022

Cited by 2 | Viewed by 1803

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence that includes FP-RMS, harboring the fusion oncoprotein PAX3/7-FOXO1 and FN-RMS, often mutant in the RAS pathway. Risk stratifications of RMS patients determine different prognostic groups and related therapeutic treatment. Current [...] Read more.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence that includes FP-RMS, harboring the fusion oncoprotein PAX3/7-FOXO1 and FN-RMS, often mutant in the RAS pathway. Risk stratifications of RMS patients determine different prognostic groups and related therapeutic treatment. Current multimodal therapeutic strategies involve surgery, chemotherapy (CHT) and radiotherapy (RT), but despite the deeper knowledge of response mechanisms underpinning CHT treatment and the technological improvements that characterize RT, local failures and recurrence frequently occur. This review sums up the RMS classification and the management of RMS patients, with special attention to RT treatment and possible radiosensitizing strategies for RMS tumors. Indeed, RMS radioresistance is a clinical problem and further studies aimed at dissecting radioresistant molecular mechanisms are needed to identify specific targets to hit, thus improving RT-induced cytotoxicity. Full article

(This article belongs to the Special Issue Sarcoma)

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15 pages, 739 KiB

Open AccessReview

Human Gammaherpesvirus 8 Oncogenes Associated with Kaposi’s Sarcoma

by Amanda de Oliveira Lopes, Pedro do Nascimento Marinho, Letícia d’Ambrosio de Souza Medeiros and Vanessa Salete de Paula

Int. J. Mol. Sci. 2022, 23(13), 7203; https://doi.org/10.3390/ijms23137203 - 29 Jun 2022

Cited by 8 | Viewed by 2322

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human gammaherpesvirus 8 (HHV-8), contains oncogenes and proteins that modulate various cellular functions, including proliferation, differentiation, survival, and apoptosis, and is integral to KSHV infection and oncogenicity. In this review, we describe the most important KSHV [...] Read more.

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human gammaherpesvirus 8 (HHV-8), contains oncogenes and proteins that modulate various cellular functions, including proliferation, differentiation, survival, and apoptosis, and is integral to KSHV infection and oncogenicity. In this review, we describe the most important KSHV genes [ORF 73 (LANA), ORF 72 (vCyclin), ORF 71 or ORFK13 (vFLIP), ORF 74 (vGPCR), ORF 16 (vBcl-2), ORF K2 (vIL-6), ORF K9 (vIRF 1)/ORF K10.5, ORF K10.6 (vIRF 3), ORF K1 (K1), ORF K15 (K15), and ORF 36 (vPK)] that have the potential to induce malignant phenotypic characteristics of Kaposi’s sarcoma. These oncogenes can be explored in prospective studies as future therapeutic targets of Kaposi’s sarcoma. Full article

(This article belongs to the Special Issue Sarcoma)

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12 pages, 270 KiB

Open AccessReview

Therapeutic Targets and Emerging Treatments in Advanced Chondrosarcoma

by Shinji Miwa, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Kentaro Igarashi and Hiroyuki Tsuchiya

Int. J. Mol. Sci. 2022, 23(3), 1096; https://doi.org/10.3390/ijms23031096 - 20 Jan 2022

Cited by 17 | Viewed by 3280

Abstract

Due to resistance to standard anticancer agents, it is difficult to control the disease progression in patients with metastatic or unresectable chondrosarcoma. Novel therapeutic approaches, such as molecule-targeting drugs and immunotherapy, are required to improve clinical outcomes in patients with advanced chondrosarcoma. Recent [...] Read more.

Due to resistance to standard anticancer agents, it is difficult to control the disease progression in patients with metastatic or unresectable chondrosarcoma. Novel therapeutic approaches, such as molecule-targeting drugs and immunotherapy, are required to improve clinical outcomes in patients with advanced chondrosarcoma. Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcoma, including IDH1/2 and COL2A1. Several molecule-targeting agents and immunotherapies have shown favorable antitumor activity in clinical studies in patients with advanced chondrosarcomas. This review summarizes recent basic studies on biomarkers and molecular targets and recent clinical studies on the treatment of chondrosarcomas. Full article

(This article belongs to the Special Issue Sarcoma)

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