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Cancers Jan 2021Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it... (Review)
Review
Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from the serosal surface of the abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within three years. The dismal survival makes DSRCT an orphan disease with an urgent need for new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors was evaluated by small trials. Recent studies using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.
PubMed: 33525546
DOI: 10.3390/cancers13030498 -
Nature Communications Aug 2023The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the...
The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define mechanisms involved, here we treat established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). Depletion of FAP CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR T cells and to anti-PD-1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape by reducing myeloid cell accumulation and increasing endogenous CD8 T cell and NK cell infiltration. These data provide strong rationale for combining tumor stroma- and malignant cell-targeted therapies to be tested in clinical trials.
Topics: Humans; Immunosuppression Therapy; Immunotherapy; Cell Movement; Pancreatic Neoplasms; CD8-Positive T-Lymphocytes
PubMed: 37607999
DOI: 10.1038/s41467-023-40850-5 -
Cancer Letters Nov 2023Pancreatic cancer remains one of the deadliest cancers with extremely high mortality rate, and the number of cases is expected to steadily increase with time. Pancreatic... (Review)
Review
Pancreatic cancer remains one of the deadliest cancers with extremely high mortality rate, and the number of cases is expected to steadily increase with time. Pancreatic cancer is refractory to conventional cancer treatment options, like chemotherapy and radiotherapy, and commercialized immunotherapeutics, owing to its immunosuppressive and desmoplastic phenotype. Due to these reasons, development of an innovative treatment option that can overcome these challenges posed by the pancreatic tumor microenvironment (TME) is in an urgent need. The present review aims to summarize the evolution of oncolytic adenovirus (oAd) engineering and usage as therapeutics (either monotherapy or combination therapy) over the last decade to overcome these hurdles to instigate a potent antitumor effect against desmoplastic and immunosuppressive pancreatic cancer.
Topics: Humans; Oncolytic Virotherapy; Oncolytic Viruses; Adenoviridae; Pancreatic Neoplasms; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37940067
DOI: 10.1016/j.canlet.2023.216456 -
Journal of Clinical Medicine Nov 2022Cholangiocarcinoma (CCA) is an aggressive neoplasia with an increasing incidence and mortality. It is characterized by a strong desmoplastic stroma surrounding cancer... (Review)
Review
Cholangiocarcinoma (CCA) is an aggressive neoplasia with an increasing incidence and mortality. It is characterized by a strong desmoplastic stroma surrounding cancer cells. Cancer-associated fibroblasts (CAFs) are the main cell type of CCA stroma and they have an important role in modulating cancer microenvironments. CAFs originate from multiple lines of cells and mainly consist of fibroblasts and alpha-smooth muscle actin (α-SMA) positive myofibroblast-like cells. The continuous cross-talking between CCA cells and desmoplastic stroma is permitted by CAF biochemical signals, which modulate a number of pathways. Stromal cell-derived factor-1 expression increases CAF recruitment to the tumor reactive stroma and influences apoptotic pathways. The Bcl-2 family protein enhances susceptibility to CAF apoptosis and PDGFRβ induces fibroblast migration and stimulates tumor lymphangiogenesis. Many factors related to CAFs may influence CCA prognosis. For instance, a better prognosis is associated with IL-33 expression and low stromal IL-6 (whose secretion is stimulated by microRNA). In contrast, a worst prognosis is given by the expression of PDGF-D, podoplanin, SDF-1, α-SMA high expression, and periostin. The maturity phenotype has a prognostic relevance too. New therapeutic strategies involving CAFs are currently under study. Promising results are obtained with anti-PlGF therapy, nintedanib (BIBF1120), navitoclax, IPI-926, resveratrol, and controlled hyperthermia.
PubMed: 36362726
DOI: 10.3390/jcm11216498 -
Actas Dermo-sifiliograficas Jan 2022Desmoplastic melanoma (DM) accounts for 0.4% to 4% of all melanomas. These skin tumors are mainly formed by amelanotic spindled melanocytes immersed in an abundant... (Review)
Review
Desmoplastic melanoma (DM) accounts for 0.4% to 4% of all melanomas. These skin tumors are mainly formed by amelanotic spindled melanocytes immersed in an abundant collagen stroma and are classified as pure when the desmoplastic component accounts for at least 90% of the invasive tumor and as mixed or combined otherwise. DMs are more common in men (male to female ratio, 1.7 to 2:1), and the mean age at diagnosis is 66 to 69 years. The tumors tend to occur in chronically sun-exposed areas, often in association with lentigo maligna, and are difficult to recognize because they can resemble a scar, presenting as a firm, unpigmented papule or plaque with poorly defined borders. DMs also have a strong tendency to recur locally, and pure variants rarely spread to the lymph nodes. Nonetheless, recently published series suggest that patients with DM have a similar prognosis to those with nondesmoplastic melanoma of the same thickness. The clinical management of DM varies in certain aspects from that of other melanomas and is reviewed in this article.
PubMed: 35249710
DOI: 10.1016/j.ad.2021.06.004 -
Autopsy & Case Reports 2021The modern era has brought an appreciation that renal cell carcinoma (RCC) includes diverse subtypes derived from the various parts of the nephron, each with its...
The modern era has brought an appreciation that renal cell carcinoma (RCC) includes diverse subtypes derived from the various parts of the nephron, each with its distinctive genetic basis and tumor biology. Carcinoma of the collecting ducts of Bellini (CDC) is a rare subtype of RCC, with a predictably poor prognosis. This rare subtype represents less than 1% of all kidney carcinomas. It derives from presumably numerous chromosomal losses. It is of chief importance to differentiate CDC from other types of renal cell cancer. Typically, it is characterized by a firm, centrally located tumor with infiltrative borders. Regarding the histopathologic characteristics, we can find complex, highly infiltrative cords with inflamed (desmoplastic) stroma, with high-grade nuclei and mitoses. Most reported cases of CDC had been high grade, advanced stage, and unresponsive to conventional therapies. This rare form of disease highlights the importance of multidisciplinary teams in the management of cancer patients.
PubMed: 34277493
DOI: 10.4322/acr.2020.230 -
Melanoma Management Sep 2021
PubMed: 34900219
DOI: 10.2217/mmt-2020-0013 -
Gastroenterology Jun 2020Although the estimated time for development of pancreatic ductal adenocarcinoma (PDA) is more than 20 years, PDAs are usually detected at late, metastatic stages. PDAs... (Review)
Review
Although the estimated time for development of pancreatic ductal adenocarcinoma (PDA) is more than 20 years, PDAs are usually detected at late, metastatic stages. PDAs develop from duct-like cells through a multistep carcinogenesis process, from low-grade dysplastic lesions to carcinoma in situ and eventually to metastatic disease. This process involves gradual acquisition of mutations in oncogenes and tumor suppressor genes, as well as changes in the pancreatic environment from a pro-inflammatory microenvironment that favors the development of early lesions, to a desmoplastic tumor microenvironment that is highly fibrotic and immune suppressive. This review discusses our current understanding of how PDA originates.
Topics: Animals; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Lineage; Cell Transformation, Neoplastic; Disease Progression; Genetic Predisposition to Disease; Humans; Mutation; Pancreatic Neoplasms; Time Factors; Tumor Microenvironment
PubMed: 32199881
DOI: 10.1053/j.gastro.2020.02.059