Heterozygous Tumor Suppressor Microenvironment in Cancer Development

Brosseau, Jean Philippe; Le, Lu Q.

doi:10.1016/j.trecan.2019.07.004

Cited by 8 publications

(5 citation statements)

References 33 publications

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“…Mice with a heterozygous mutation for Nf1 (mimicking NF1 patients) develop neurofibroma faster than their wild type littermates [3][4][5]. The cellular and molecular mechanisms by which the microenvironment promotes neurofibroma development, however, is unclear [6]. The neurofibroma microenvironment is composed of fibroblasts, pericytes, immune cells (such as macrophages, mast cells), and blood vessels mingled in a thick collagenous matrix.…”

Section: Introductionmentioning

confidence: 99%

Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing

Brosseau

Sathe

Wang

et al. 2021

acta neuropathol commun

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Neurofibromatosis Type I (NF1) is a neurocutaneous genetic syndrome characterized by a wide spectrum of clinical presentations, including benign peripheral nerve sheath tumor called neurofibroma. These tumors originate from the Schwann cell lineage but other cell types as well as extracellular matrix (ECM) in the neurofibroma microenvironment constitute the majority of the tumor mass. In fact, collagen accounts for up to 50% of the neurofibroma’s dry weight. Although the presence of collagens in neurofibroma is indisputable, the exact repertoire of ECM genes and ECM-associated genes (i.e. the matrisome) and their functions are unknown. Here, transcriptome profiling by single-cell RNA sequencing reveals the matrisome of human cutaneous neurofibroma (cNF). We discovered that classic pro-fibrogenic collagen I myofibroblasts are rare in neurofibroma. In contrast, collagen VI, a pro-tumorigenic ECM, is abundant and mainly secreted by neurofibroma fibroblasts. This study also identified potential cell type-specific markers to further elucidate the biology of the cNF microenvironment.

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Section: Introductionmentioning

confidence: 99%

Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing

Brosseau

Sathe

Wang

et al. 2021

acta neuropathol commun

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“…Whether STK11 haploinsufficiency is enough to initiate tumor development in humans is unknown, but has been demonstrated in mouse models, and may possibly be related to a heterozygous tumor suppressor gene microenvironment. [21][22][23] The differential diagnosis is broad, as evidenced by the variety of diagnoses rendered both in the literature and the cases presented here. The most frequent diagnosis was FATWO, which is fitting as they are usually paratubal, show a variety of histologic patterns, and have a nonspecific immunoprofile.…”

Section: Discussionmentioning

confidence: 89%

“…Notably, 3 tumors (cases 7, 12, and 15) were haploinsufficient for STK11. Whether STK11 haploinsufficiency is enough to initiate tumor development in humans is unknown, but has been demonstrated in mouse models, and may possibly be related to a heterozygous tumor suppressor gene microenvironment 21–23…”

Section: Discussionmentioning

confidence: 99%

A Distinctive Adnexal (Usually Paratubal) Neoplasm Often Associated With Peutz-Jeghers Syndrome and Characterized by STK11 Alterations (STK11 Adnexal Tumor)

Bennett

Young

Howitt

et al. 2021

American Journal of Surgical Pathology

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We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 years (median=39 y) and the tumors from 4.5 to 25.5 cm (median=11 cm). Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median=9/10 HPFs). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2-40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive, while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphologic, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome.

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“…Somatic mutations in NF1, CDKN2A/B, and PRC2 can be found in the majority of MPNST cases, irrespective of the origin. However, the genetics of those neoplasms are complex and involve not only mutations in single genes but also epigenetic changes and disorders within the tumor microenvironment contributing to malignant transformation [13]. The basis for the development of NF1 and the factor increasing the risk of MPNST are the germline mutations in the tumor suppressor gene NF1 (neurofibromin 1) located on chromosome 17q11.2 [14].…”

Section: Mpnst Biology and Geneticsmentioning

confidence: 99%

Malignant peripheral nerve sheath tumor — from genetics to multidisciplinary treatment

Czarnecka,

Chmiel,

Sobczuk

et al. 2024

Oncol Clin Pract

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Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma (STS); it originates from nervous tissue and typically develops in proximity to nerve trunks in the limbs and trunk. These tumors, constituting approximately 5% of soft tissue sarcomas, can either form spontaneously or arise from pre-existing neurofibromas. The majority (90%) of cases occur in individuals between the 2 nd and 5 th decades of life. The main risk factor for MPNST is von Recklinghausen disease (type 1 neurofibromatosis). The cornerstone of MPNST management involves radical surgical measures, specifically tumor excision within healthy tissue boundaries (wide local excision), which is complemented by adjuvant radiotherapy. In case of metastatic disease, palliative chemotherapy employing doxorubicin or a combination of doxorubicin and ifosfamide is utilized. Approximately 25-30% of patients experience clinical improvement after chemotherapy. Looking ahead, advancements in research on molecular biology may lead to the development of inhibitors demonstrating greater efficacy than traditional chemotherapy for MPNST patients. At present, ongoing clinical trials of the therapeutic management of MPNST encompass pembrolizumab, the combination of nivolumab with ipilimumab, pexydartinib (an inhibitor targeting KIT, CSF1R, and FLT3) in conjunction with sirolimus, sapanisertib (a TORC1/2 inhibitor), or LOXO-195 (an inhibitor of neurotrophic tyrosine kinase receptors NTRK type 1, 2, and 3).

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Heterozygous Tumor Suppressor Microenvironment in Cancer Development

Cited by 8 publications

References 33 publications

Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing

Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing

A Distinctive Adnexal (Usually Paratubal) Neoplasm Often Associated With Peutz-Jeghers Syndrome and Characterized by STK11 Alterations (STK11 Adnexal Tumor)

Malignant peripheral nerve sheath tumor — from genetics to multidisciplinary treatment

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