The Extracellular Matrix in Soft Tissue Sarcomas: Pathobiology and Cellular Signalling

Soft tissue sarcomas are rare cancers of mesenchymal origin or differentiation comprising over 70 different histological subtypes. Due to their mesenchymal differentiation, sarcomas are thought to produce and deposit large quantities of extracellular matrix (ECM) components. Interactions between ECM ligands and their corresponding adhesion receptors such as the integrins and the discoidin domain receptors play key roles in driving many fundamental oncogenic processes including uncontrolled proliferation, cellular invasion and altered metabolism. In this review, we focus on emerging studies that describe the key ECM components commonly found in soft tissue sarcomas and discuss preclinical and clinical evidence outlining the important role that these proteins and their cognate adhesion receptors play in sarcomagenesis. We conclude by providing a perspective on the need for more comprehensive in-depth analyses of both the ECM and adhesion receptor biology in multiple histological subtypes in order to identify new drug targets and prognostic biomarkers for this group of rare diseases of unmet need.

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Translating Molecular Profiling of Soft Tissue Sarcomas into Daily Clinical Practice

Diagnostics ◽

10.3390/diagnostics11030512 ◽

2021 ◽

Vol 11 (3) ◽

pp. 512

Author(s):

Celine Jacobs ◽

Lore Lapeire

Keyword(s):

Soft Tissue ◽

Unmet Need ◽

Soft Tissue Sarcomas ◽

Molecular Profiling ◽

Point Of View ◽

Molecular Techniques ◽

Mesenchymal Tumors ◽

The Past ◽

Cancer Types ◽

Sarcoma Treatment

Soft tissue sarcomas are a group of rare mesenchymal tumors with more than 70 subtypes described. Treatment of these subtypes in an advanced setting is mainly according to a one-size-fits-all strategy indicating a high unmet need of new and more targeted therapeutic options in order to optimize survival. The introduction of advanced molecular techniques in cancer has led to better diagnostics and identification of new therapeutic targets, leading to more personalized treatment and improved prognosis for several cancer types. In sarcoma, a likewise evolution is seen, albeit at a slower pace. This manuscript describes how in the past years advanced molecular profiling in soft tissue sarcomas was able to identify specific and often pathognomonic aberrations, deferring standard sarcoma treatment in favor of more targeted treatment from an oncologist’s point of view.

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High Prevalence of 5T4/Trophoblast Glycoprotein in Soft Tissue Sarcomas

Cancers ◽

10.3390/cancers13194841 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4841

Author(s):

Patrick Groothuis ◽

Nicola Penel ◽

Antoine Italiano ◽

Nuria Kotecki ◽

Fred Dijcks ◽

...

Keyword(s):

Soft Tissue ◽

Tumor Tissue ◽

Staining Method ◽

Soft Tissue Sarcomas ◽

Tissue Microarrays ◽

Histological Subtypes ◽

Scoring Method ◽

Drug Conjugates ◽

High Prevalence ◽

Quantitative Scoring

The expression of 5T4/trophoblast glycoprotein was evaluated in several histological subtypes of soft tissue sarcoma (STS) to determine whether the prevalence and level of expression of this membrane-associated glycoprotein is sufficient for use in targeted therapies. Tumor tissue microarrays containing cores from different histological subtypes of STS were stained using a standardized immunohistochemical staining method to detect 5T4; the level of staining was assessed using a semi-quantitative scoring method. No 5T4 staining was seen in the angiosarcomas and liposarcomas investigated in this study. 5T4 staining in the other STS subtypes was seen in more than 50% of cases, warranting further investigation into whether this antigen could evoke an anti-tumor immune response or can be used as target for the delivery of more potent toxins through antibody drug conjugates.

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Current status of biomarker testing in historically rare, high-unmet-need tumors: soft tissue sarcomas and thyroid cancers

Expert Review of Anticancer Therapy ◽

10.1080/14737140.2019.1682554 ◽

2019 ◽

Vol 19 (11) ◽

pp. 929-938

Author(s):

Bridgette Schroader ◽

Sheldon Kong ◽

Sibyl Anderson ◽

Todd Williamson ◽

Anthony Sireci ◽

...

Keyword(s):

Soft Tissue ◽

Unmet Need ◽

Soft Tissue Sarcomas ◽

Current Status ◽

Thyroid Cancers ◽

Biomarker Testing

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WNT/β-Catenin Pathway in Soft Tissue Sarcomas: New Therapeutic Opportunities?

Cancers ◽

10.3390/cancers13215521 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5521

Author(s):

Esther Martinez-Font ◽

Marina Pérez-Capó ◽

Oliver Vögler ◽

Javier Martín-Broto ◽

Regina Alemany ◽

...

Keyword(s):

Soft Tissue ◽

Wnt Signaling ◽

Signaling Pathway ◽

Drug Targets ◽

Current Knowledge ◽

Locally Advanced ◽

Wnt Signaling Pathway ◽

Soft Tissue Sarcomas ◽

Molecular Alterations ◽

New Therapeutic Approaches

Soft tissue sarcomas (STS) are a very heterogeneous group of rare tumors, comprising more than 50 different histological subtypes that originate from mesenchymal tissue. Despite their heterogeneity, chemotherapy based on doxorubicin (DXR) has been in use for forty years now and remains the standard first-line treatment for locally advanced unresectable or metastatic STS, although overall survival could not be improved by combination with other chemotherapeutics. In this sense, the development of new therapeutic approaches continues to be a largely unmatched goal. The WNT/β-catenin signaling pathway is involved in various fundamental processes for embryogenic development, including the proliferation and differentiation of mesenchymal stem cells. Although the role of this pathway has been widely researched in neoplasms of epithelial origin, little is known about its relevance for mesenchymal neoplasms. This review covers the most important molecular alterations of the WNT signaling pathway in STS. The detection of these alterations and the understanding of their functional consequences for those pathways controlling sarcomagenesis development and progression are crucial to broaden the current knowledge about STS as well as to identify novel drug targets. In this regard, the current therapeutic options and drug candidates to modulate WNT signaling, which are usually classified by their interaction site upstream or downstream of β-catenin, and their presumable clinical impact on STS are also discussed.

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Gene expression identifies heterogeneity of soft tissue sarcomas

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9574 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9574-9574

Author(s):

K. M. Skubitz ◽

S. Pambuccian ◽

A. P. Skubitz

Keyword(s):

Gene Expression ◽

Soft Tissue ◽

Expression Patterns ◽

Soft Tissue Sarcomas ◽

Gene Expression Patterns ◽

Histological Subtypes ◽

Normal Tissues ◽

Gene Sets ◽

Histological Appearance ◽

Gene Logic

9574 Background: Soft tissue sarcomas (STS) exhibit heterogeneity in their clinical behavior, even within histological subtypes. Histological appearance is determined by gene expression. However, metastatic propensity, tumor growth, and response to chemotherapy may be determined by gene expression patterns that do not correlate well with morphology. One approach to identify heterogeneity is to search for markers that correlate with differences in tumor behavior. Alternatively, subsets may be identified based on gene expression patterns independent of knowledge of clinical outcome. We have reported gene expression patterns that distinguish two broad classes of clear cell renal carcinoma (ccRCC) independent of histological appearance, and other patterns that can distinguish heterogeneity of serous ovarian carcinoma (OVCA). Methods: In this study, gene expression in 41 samples of STS (including malignant fibrous histiocytoma (MFH), leiomyosarcoma, liposarcoma, and synovial sarcoma), 12 samples of fibromatosis, and 17 normal tissues was determined at Gene Logic Inc. (Gaithersburg, MD) using Affymetrix GeneChip U_133 arrays containing approximately 40,000 genes/ESTs. Gene expression analysis was performed with the Gene Logic Genesis Enterprise System Software. Results: Hierarchical clustering using two gene sets, one that distinguished two subsets of ccRCC, and a second set that distinguished two subsets of OVCA, both generated subgroups within the STS that for some, but not all, subtypes correlated with histology, and also suggested the existence of subsets of MFH. Both gene sets also identified the same two subsets of the fibromatosis samples. In addition, genes expressed uniquely in MFH, leiomyosarcomas, and liposarcomas among these and 512 samples from 17 other normal tissue types were identified. Conclusions: The ability to sub-classify histological subtypes of STS, including identifying possible subsets of MFH, using gene sets derived from studies of two different carcinomas suggests that these subgroups may have biological significance. Some of the genes identified as over-expressed in particular subsets of STS compared with a variety of normal tissues may reflect possible targets to which anti-tumor therapy could be directed, and may also be useful for sub-classification of STS. No significant financial relationships to disclose.

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Immune-Based Therapies for Sarcoma

Sarcoma ◽

10.1155/2011/438940 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 25

Author(s):

Seth M. Pollack ◽

Elizabeth T. Loggers ◽

Eve T. Rodler ◽

Cassian Yee ◽

Robin L. Jones

Keyword(s):

Clinical Practice ◽

Soft Tissue ◽

Systemic Therapy ◽

Unmet Need ◽

Soft Tissue Sarcomas ◽

Exact Role ◽

Cancer Testis Antigens ◽

Standard Clinical Practice ◽

Tumor Types ◽

Cancer Testis

Immunotherapy has shown promise in a number of tumor types, but its exact role in sarcoma remains to be defined. Advanced bone and soft tissue sarcomas are challenging diseases to treat with an unmet need for effective systemic therapy. Previous reports have suggested that immune-based treatments may be effective in sarcoma, but such approaches have not yet become part of standard clinical practice. A number of sarcoma subtypes express targets known as cancer testis antigens and hence may be excellent targets for immunotherapy. This paper will focus on the recent advances and understanding of cancer testis antigens in sarcoma and also clinical data of immunotherapeutic approaches in these diseases.

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Defining the Extracellular Matrix of Rhabdomyosarcoma

10.21203/rs.3.rs-38028/v1 ◽

2020 ◽

Author(s):

Xiaolei Lian ◽

J. Steffan Bond ◽

Narendra Bharathy ◽

Sergei P. Boudko ◽

Elena Pokidysheva ◽

...

Keyword(s):

Extracellular Matrix ◽

Soft Tissue ◽

Structural Integrity ◽

Quaternary Structure ◽

Soft Tissue Sarcomas ◽

Tissue Microarrays ◽

Cell Of Origin ◽

Term Survival ◽

Long Term Survival

Abstract Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood with a propensity to metastasize. Current treatment for patients with RMS includes conventional systemic chemotherapy, radiation therapy and surgical resection; nevertheless, little to no improvement in long term survival has been achieved in decades – underlining the need for target discovery and new therapeutic approaches to targeting tumor cells or the tumor microenvironment.Methods:To evaluate cross-species sarcoma extracellular matrix production, we have used murine models which feature knowledge of the myogenic cell-of-origin. With focus on the RMS/undifferentiated pleomorphic sarcoma (UPS) continuum, we have constructed tissue microarrays of 48 murine and 4 human sarcomas to analyze expression of 7 different collagens, fibrillins and collagen-modifying proteins, with cross-correlation to RNA deep sequencing.Results:We have uncovered that RMS produces increased expression of type XVIII collagen alpha 1 (COL18A1), which is clinically associated with decreased long-term survival. We have also identified significantly increased RNA expression of COL4A1, FBN2, PLOD1 and PLOD2 in human RMS relative to normal skeletal muscle.Conclusion:These results complement recent studies investigating whether soft tissue sarcomas utilize collagens, fibrillins and collagen-modifying enzymes to alter the structural integrity of surrounding host extracellular matrix/collagen quaternary structure resulting in improved ability to improve the ability to invade regionally and metastasize, for which therapeutic targeting is possible.

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Defining the Extracellular Matrix of Rhabdomyosarcoma

Frontiers in Oncology ◽

10.3389/fonc.2021.601957 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaolei Lian ◽

J. Steffan Bond ◽

Narendra Bharathy ◽

Sergei P. Boudko ◽

Elena Pokidysheva ◽

...

Keyword(s):

Extracellular Matrix ◽

Soft Tissue ◽

Structural Integrity ◽

Quaternary Structure ◽

Soft Tissue Sarcomas ◽

Tissue Microarrays ◽

Cell Of Origin ◽

Term Survival ◽

Long Term Survival

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood with a propensity to metastasize. Current treatment for patients with RMS includes conventional systemic chemotherapy, radiation therapy, and surgical resection; nevertheless, little to no improvement in long term survival has been achieved in decades—underlining the need for target discovery and new therapeutic approaches to targeting tumor cells or the tumor microenvironment. To evaluate cross-species sarcoma extracellular matrix production, we have used murine models which feature knowledge of the myogenic cell-of-origin. With focus on the RMS/undifferentiated pleomorphic sarcoma (UPS) continuum, we have constructed tissue microarrays of 48 murine and four human sarcomas to analyze expression of seven different collagens, fibrillins, and collagen-modifying proteins, with cross-correlation to RNA deep sequencing. We have uncovered that RMS produces increased expression of type XVIII collagen alpha 1 (COL18A1), which is clinically associated with decreased long-term survival. We have also identified significantly increased RNA expression of COL4A1, FBN2, PLOD1, and PLOD2 in human RMS relative to normal skeletal muscle. These results complement recent studies investigating whether soft tissue sarcomas utilize collagens, fibrillins, and collagen-modifying enzymes to alter the structural integrity of surrounding host extracellular matrix/collagen quaternary structure resulting in improved ability to improve the ability to invade regionally and metastasize, for which therapeutic targeting is possible.

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ErbB Receptors as Prognostic and Therapeutic Drug Targets in Bone and Soft Tissue Sarcomas

Cancer Investigation ◽

10.3109/07357907.2014.964409 ◽

2014 ◽

Vol 32 (10) ◽

pp. 533-542 ◽

Cited By ~ 2

Author(s):

Hongsheng Wang ◽

Qingbo Yang ◽

Zeze Fu ◽

Dongqing Zuo ◽

Yingqi Hua ◽

...

Keyword(s):

Soft Tissue ◽

Drug Targets ◽

Soft Tissue Sarcomas ◽

Erbb Receptors ◽

Therapeutic Drug

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Adult Head and Neck Soft Tissue Sarcomas: Treatment and Outcome

Sarcoma ◽

10.1155/2008/654987 ◽

2008 ◽

Vol 2008 ◽

pp. 1-5 ◽

Cited By ~ 18

Author(s):

Rabindra P. Singh ◽

Robert J. Grimer ◽

Nabina Bhujel ◽

Simon R. Carter ◽

Roger M. Tillman ◽

...

Keyword(s):

Overall Survival ◽

Soft Tissue ◽

Local Recurrence ◽

Head And Neck ◽

Metastatic Disease ◽

Tumour Size ◽

Soft Tissue Sarcomas ◽

Histological Subtypes ◽

Median Size ◽

Adult Head

We have retrospectively analysed the experience of a musculoskeletal oncological unit in the management of adult head and neck soft tissue sarcomas from 1990 to 2005. Thirty-six patients were seen, of whom 24 were treated at this unit, the remainder only receiving advice. The median age of the patients was 46 years. Most of the sarcomas were deep and of high or intermediate grade with a median size of 5.5 cm. Eleven different histological subtypes were identified. Wide excision was possible only in 21% of the cases. 42% of the patients developed local recurrence and 42% developed metastatic disease usually in the lungs. Overall survival was 49% at 5 years. Tumour size was the most important prognostic factor. Adult head and neck soft tissue sarcomas have a high mortality rate with a high risk of local recurrence and metastatic disease. The rarity of the disease would suggest that centralisation of care could lead to increased expertise and better outcomes.

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