Targeting STAT3 signaling pathway in cancer by agents derived from Mother Nature

Tumor suppressive protein phosphatases in human cancer: Emerging targets for therapeutic intervention and tumor stratification.

Rationale: Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available We hence investigated the immune subtypes of PCNSL and their association with molecular signaling and survival Methods: Analysis of PCNSL transcriptomes (sequencing, n = 20; microarrays, n = 34) Integrated correlation analysis and signaling pathway topology enabled us to infer intercellular interactions Immunohistopathology and digital imaging were used to validate bioinformatic results Results: Transcriptomics revealed three immune subtypes: immune-rich, poor, and intermediate The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling, eg, IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer WNT/β-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression A ligand-receptor intercellular network revealed high expression of two immune checkpoints, ie, CTLA-4/CD86 and TIM-3/LAGLS9 TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL Conclusion: Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy Moreover, TIM-3 protein should be considered an axis for future therapeutic development

The immune contexture of primary central nervous system diffuse large B cell lymphoma associates with patient survival and specific cell signaling.

Despite a large number of therapeutic options available, malignant melanoma remains a highly fatal disease, especially in its metastatic forms. The oncogenic role of protein tyrosine phosphatases (PTPs) is becoming increasingly clear, paving the way for novel antitumor treatments based on their inhibition. In this review, we present the oncogenic PTPs contributing to melanoma progression and we provide, where available, a description of new inhibitory strategies designed against these enzymes and possibly useful in melanoma treatment. Considering the relevance of the immune infiltrate in supporting melanoma progression, we also focus on the role of PTPs in modulating immune cell activity, identifying interesting therapeutic options that may support the currently applied immunomodulating approaches. Collectively, this information highlights the value of going further in the development of new strategies targeting oncogenic PTPs to improve the efficacy of melanoma treatment.

Oncogenic Tyrosine Phosphatases: Novel Therapeutic Targets for Melanoma Treatment.

The Src homology region 2 domain-containing phosphatase-1 (SHP1) is a critical negative regulator involved in the JAK/STAT signaling pathway. The SHP1 gene has been proposed as a candidate tumor suppressor in solid and hematological malignancies and promoter methylation is an important biological process in controlling tumorigenesis. However, the detailed roles of SHP1 promoter methylation in the pathogenesis of primary central nervous system lymphoma (PCNSL) is largely unknown. In the present study, we evaluated the correlation between SHP1 expression and promoter methylation in patients with PCNSL. Thirty-three patients with PCNSL were included. We evaluated SHP1 protein expression levels by immunohistochemistry and the SHP1 promoter methylation profile by pyrosequencing analysis. For cases (n=8) with a good yield of total protein, SHP1 phosphorylation (pSHP1) and STAT3 protein expression levels were further analyzed by western blot analysis to uncover the molecular impact of SHP1 promoter methylation on downstream signaling pathways. In this study, a lower expression of SHP1 protein level was observed in 16/33 cases (48.5%) of PCNSL. SHP1 promoter methylation was predominant in 29/33 cases (87.9%) with a mean methylation level of 31.7±36.5%. The mean methylation level of the SHP1 promoter was significantly elevated in patients with a lower SHP1 protein expression, compared with those showing a higher SHP1 protein expression (50.3±38.9 vs. 14.2±24.0%, p=0.004). Further analysis showed that SHP1 protein expression was significantly decreased in patients with a higher SHP1 promoter methylation status (p=0.001), and such attenuation was correlated with a downregulation of pSHP1 (p=0.005) and an upregulation of STAT3 protein expression (p=0.020). Our data demonstrated that epigenetic alterations in the promoter region downregulated SHP1 expression in PCNSL patients. SHP1 promoter methylation was correlated with tyrosine phosphorylation and activation of transcription factor STAT3, which may contribute to the pathogenesis of PCNSL. Therapeutical regimens with epigenetic modifiers may be a potential option for patients with PCNSL.

https://www.spandidos-publications.com/10.3892/or.2016.5308/download

Promoter methylation attenuates SHP1 expression and function in patients with primary central nervous system lymphoma.

Myeloid sarcoma is a rare extramedullary malignant tumor, which is often accompanied by the development of systemic myeloid disease at various sites. The involvement of the central nervous system is uncommon and spinal cord compression is particularly rare. In November 2012, a 27-year-old male presented with a paroxysmal headache, accompanied by nausea and vomiting, which had persisted for one year, and eyesight deterioration that had been apparent for five months. Magnetic resonance imaging (MRI) indicated a space-occupying disorder, a craniotomy to resect the brain tumor was undertaken, the pathological diagnosis of which was myeloid sarcoma. Two months after receiving 40 Gy of radiotherapy, the patient experienced numbness of the right thigh. MRI of the lumbar spinal canal revealed a mass involved both inside and outside the lumbar spinal canal. Pathological examination of the mass following resection also indicated myeloid sarcoma. Immunohistochemical analysis was positive for the ETO fusion gene in the bone marrow. Following six cycles of chemotherapy treatment, the patient achieved complete remission. At present, the patient is stable and is attending follow-up examinations regularly.

/pdf/isolated-primary-intracranial-myeloid-sarcoma-with-48tfswz89h.pdf

Isolated primary intracranial myeloid sarcoma with neuromeningeal infiltration: A case report

Iatrogenic cervical hematoma caused by accidental injury of superior thyroid artery: A rare complication of internal jugular vein catheterization.

BACKGROUND
Histopathological features and molecular biomarkers have been studied as potential prognostic factors.


OBJECTIVE
To investigate the clinical features, molecular phenotypes, and survival prognosis of isocitrate dehydrogenase (IDH)-mutant (IDHmt) gliomas with histone H3 alterations (H3-alterations).


METHODS
A total of 236 and 657 patients with whole-exome sequencing data were separately collected from the Chinese Glioma Genome Atlas and The Cancer Genome Atlas databases. Survival analysis of patients with glioma was performed using Kaplan-Meier survival curves stratified by histone H3 status. Univariate and multivariate analyses were used to identify the associations between histone H3 status and other clinicopathological factors with survival in patients with IDH-mutant gliomas.


RESULTS
Diffuse gliomas with H3 alterations are more likely to be high grade in 2 cohorts (P = .025 and P = .021, respectively). IDHmt glioma patients with H3-alteration had significantly less life expectancy than histone H3 wild-type (P = .041 and P = .008, respectively). In the Chinese Glioma Genome Atlas cohort, Karnofsky performance scores ≤ 80 (HR 2.394, 95% CI 1.257-4.559, P = .008), extent of resection (HR 0.971, 95% CI 0.957-0.986, P < .001), high WHO grade (HR 6.938, 95% CI 2.787-17.269, P < .001), H3-alteration (HR 2.482, 95% CI 1.183-4.981, P = .016), and 1p/19q codeletion (HR 0.169, 95% CI 0.073-0.390, P < .001) were independently associated with IDHmt gliomas. In the The Cancer Genome Atlas cohort, age (HR 1.034, 95% CI 1.008-1.061, P = .010), high WHO grade (HR 2.365, 95% CI 1.263-4.427, P = .007), and H3-alteration (HR 2.501, 95% CI 1.312-4.766, P = .005) were independently associated with IDHmt gliomas.


CONCLUSION
Identification and assessment of histone H3 status in clinical practice might help improve prognostic prediction and develop therapeutic strategies for these patient subgroups.

Diffuse Isocitrate Dehydrogenase-Mutant Gliomas With Histone H3 Alterations Are Distinguished by Unique Clinical Characteristics, Molecular Expression Profile, and Survival Prognosis.

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Papers

Promoter methylation attenuates SHP1 expression and function in patients with primary central nervous system lymphoma.

Isolated primary intracranial myeloid sarcoma with neuromeningeal infiltration: A case report

Iatrogenic cervical hematoma caused by accidental injury of superior thyroid artery: A rare complication of internal jugular vein catheterization.

Diffuse Isocitrate Dehydrogenase-Mutant Gliomas With Histone H3 Alterations Are Distinguished by Unique Clinical Characteristics, Molecular Expression Profile, and Survival Prognosis.