A Novel Strategy for the Diagnosis of Pulmonary High-Grade Neuroendocrine Tumor

Correctly diagnosing a histologic type of lung cancer is important for selecting the appropriate treatment because the aggressiveness, chemotherapy regimen, surgical approach, and prognosis vary significantly among histologic types. Pulmonary NETs, which are characterized by neuroendocrine morphologies, represent approximately 20% of all lung cancers. In particular, high-grade neuroendocrine tumors (small cell lung cancer and large cell neuroendocrine tumor) are highly proliferative cancers that have a poorer prognosis than other non-small cell lung cancers. The combination of hematoxylin and eosin staining, Ki-67, and immunostaining of classic neuroendocrine markers, such as chromogranin A, CD56, and synaptophysin, are normally used to diagnose high-grade neuroendocrine tumors; however, they are frequently heterogeneous. This article reviews the diagnostic methods of lung cancer diagnosis focused on immunostaining. In particular, we describe the usefulness of immunostaining by Stathmin-1, which is a cytosolic phosphoprotein and a key regulator of cell division due to its microtubule depolymerization in a phosphorylation-dependent manner, for the diagnosis of high-grade neuroendocrine tumors.

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SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer

Scientific Reports ◽

10.1038/s41598-020-75625-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Joshua T. Burgess ◽

Emma Bolderson ◽

Mark N. Adams ◽

Pascal H. G. Duijf ◽

Shu-Dong Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Cellular Proliferation ◽

Prognostic Indicator ◽

Small Cell ◽

Dependent Manner ◽

Small Cell Lung ◽

Lung Cancers ◽

Protein Levels ◽

Cellular Processes ◽

Novel Approach

Abstract SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.

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Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer

Nature Communications ◽

10.1038/s41467-021-27303-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Clemens Hinterleitner ◽

Jasmin Strähle ◽

Elke Malenke ◽

Martina Hinterleitner ◽

Melanie Henning ◽

...

Keyword(s):

Lung Cancer ◽

Checkpoint Inhibitors ◽

Blood Platelets ◽

Therapy Response ◽

Small Cell ◽

Dependent Manner ◽

Small Cell Lung ◽

Tumor Immune Evasion ◽

Lung Cancers ◽

Nsclc Patients

AbstractImmune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, however, robust markers to predict therapy response are missing. Here we show that blood platelets interact with lung cancer cells and that PD-L1 protein is transferred from tumor cells to platelets in a fibronectin 1, integrin α5β1 and GPIbα-dependent manner. Platelets from NSCLC patients are found to express PD-L1 and platelet PD-L1 possess the ability to inhibit CD4 and CD8 T-cells. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1Adj.), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Our data suggest that platelet PD-L1 reflects the collective tumor PD-L1 expression, plays important roles in tumor immune evasion and overcomes limitations of histological quantification of often heterogeneous intratumoral PD-L1 expression.

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Small cell lung cancers made from scratch

Journal of Experimental Medicine ◽

10.1084/jem.20182216 ◽

2019 ◽

Vol 216 (3) ◽

pp. 476-478 ◽

Cited By ~ 3

Author(s):

Adi F. Gazdar ◽

John D. Minna

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Embryonic Stem ◽

Small Cell ◽

High Grade ◽

Therapeutic Approaches ◽

Small Cell Lung ◽

New Approach ◽

Lung Cancers ◽

Normal Human

In this issue of JEM, Chen et al. (https://doi.org/10.1084/jem.20181155) describe a new approach for the transformation of human pluripotent embryonic stem cells (hESCs) into neuroendocrine (NE) tumors of the lung closely resembling human small cell lung cancer (SCLC). Another recent study uses a different method to transform fully differentiated normal human cells into high-grade NE tumors (Park et al. 2018. Science. https://doi.org/10.1126/science.aat5749). These approaches and their models provide important new resources for developing diagnostic, preventative, and therapeutic approaches for high-grade NE tumors.

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Protein Kinase Cε Is Overexpressed in Primary Human Non–Small Cell Lung Cancers and Functionally Required for Proliferation of Non–Small Cell Lung Cancer Cells in a p21/Cip1-Dependent Manner

Cancer Research ◽

10.1158/0008-5472.can-06-4037 ◽

2007 ◽

Vol 67 (13) ◽

pp. 6053-6063 ◽

Cited By ~ 53

Author(s):

Kyung-Mi Bae ◽

Heiman Wang ◽

Guohua Jiang ◽

Melissa G. Chen ◽

Li Lu ◽

...

Keyword(s):

Lung Cancer ◽

Protein Kinase ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cells ◽

Dependent Manner ◽

Small Cell Lung ◽

Lung Cancers

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A PHASE IIA STUDY REPOSITIONING DESIPRAMINE IN SMALL CELL LUNG CANCER AND OTHER HIGH-GRADE NEUROENDOCRINE TUMORS

Cancer Treatment and Research Communications ◽

10.1016/j.ctarc.2020.100174 ◽

2020 ◽

Vol 23 ◽

pp. 100174 ◽

Cited By ~ 1

Author(s):

Jonathan W. Riess ◽

Nadine S. Jahchan ◽

Millie Das ◽

M. Zach Koontz ◽

Pamela L. Kunz ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Neuroendocrine Tumors ◽

Cell Lung Cancer ◽

Small Cell ◽

High Grade ◽

Small Cell Lung

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Exhaustive Review on Lung Cancers: Novel Technologies

Current Medical Imaging Formerly Current Medical Imaging Reviews ◽

10.2174/1573405615666181128124528 ◽

2019 ◽

Vol 15 (9) ◽

pp. 873-883

Author(s):

Sajad Khan ◽

Shahid Ali ◽

Muhammad

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Immune Therapy ◽

Small Cell ◽

X Rays ◽

Small Cell Lung ◽

Microscopic Appearance ◽

Lung Cancers ◽

Novel Technologies

Background:Lung cancers or (Bronchogenic-Carcinomas) are the disease in certain parts of the lungs in which irresistible multiplication of abnormal cells leads to the inception of a tumor. Lung cancers consisting of two substantial forms based on the microscopic appearance of tumor cells are: Non-Small-Cell-Lung-Cancer (NSCLC) (80 to 85%) and Small-Cell-Lung-Cancer (SCLC) (15 to 20%).Discussion:Lung cancers are existing luxuriantly across the globe and the most prominent cause of death in advanced countries (USA & UK). There are many causes of lung cancers in which the utmost imperative aspect is the cigarette smoking. During the early stage, there is no perspicuous sign/symptoms but later many symptoms emerge in the infected individual such as insomnia, headache, pain, loss of appetite, fatigue, coughing etc. Lung cancers can be diagnosed in many ways, such as history, physical examination, chest X-rays and biopsy. However, after the diagnosis and confirmation of lung carcinoma, various treatment approaches are existing for curing of cancer in different stages such as surgery, radiation therapy, chemotherapy, and immune therapy. Currently, novel techniques merged that revealed advancements in detection and curing of lung cancer in which mainly includes: microarray analysis, gene expression profiling.Conclusion:Consequently, the purpose of the current analysis is to specify and epitomize the novel literature pertaining to the development of cancerous cells in different parts of the lung, various preeminent approaches of prevention, efficient diagnostic procedure, and treatments along with novel technologies for inhibition of cancerous cell growth in advance stages.

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Silibinin Regulates Tumor Progression and Tumorsphere Formation by Suppressing PD-L1 Expression in Non-Small Cell Lung Cancer (NSCLC) Cells

Cells ◽

10.3390/cells10071632 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1632

Author(s):

Alexis Rugamba ◽

Dong Young Kang ◽

Nipin Sp ◽

Eun Seong Jo ◽

Jin-Moo Lee ◽

...

Keyword(s):

Lung Cancer ◽

Growth Factor ◽

Small Cell Lung Cancer ◽

Anticancer Activity ◽

Cell Lung Cancer ◽

Small Cell ◽

Migration And Invasion ◽

Dependent Manner ◽

Molecular Signaling ◽

Small Cell Lung

Recently, natural compounds have been used globally for cancer treatment studies. Silibinin is a natural compound extracted from Silybum marianum (milk thistle), which has been suggested as an anticancer drug through various studies. Studies on its activity in various cancers are undergoing. This study demonstrated the molecular signaling behind the anticancer activity of silibinin in non-small cell lung cancer (NSCLC). Quantitative real-time polymerase chain reaction and Western blotting analysis were performed for molecular signaling analysis. Wound healing assay, invasion assay, and in vitro angiogenesis were performed for the anticancer activity of silibinin. The results indicated that silibinin inhibited A549, H292, and H460 cell proliferation in a concentration-dependent manner, as confirmed by the induction of G0/G1 cell cycle arrest and apoptosis and the inhibition of tumor angiogenesis, migration, and invasion. This study also assessed the role of silibinin in suppressing tumorsphere formation using the tumorsphere formation assay. By binding to the epidermal growth factor receptor (EGFR), silibinin downregulated phosphorylated EGFR expression, which then inhibited its downstream targets, the JAK2/STAT5 and PI3K/AKT pathways, and thereby reduced matrix metalloproteinase, PD-L1, and vascular endothelial growth factor expression. Binding analysis demonstrated that STAT5 binds to the PD-L1 promoter region in the nucleus and silibinin inhibited the STAT5/PD-L1 complex. Altogether, silibinin could be considered as a candidate for tumor immunotherapy and cancer stem cell-targeted therapy.

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Possible involvement of the Hedgehog and PDPK1–Akt pathways in the growth and migration of small-cell lung cancer

Journal of International Medical Research ◽

10.1177/03000605211016562 ◽

2021 ◽

Vol 49 (5) ◽

pp. 030006052110165

Author(s):

Naiwang Tang ◽

Bin Hu ◽

Yin Zhang ◽

Zhiwei Chen ◽

Ronghuan Yu

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Molecular Mechanisms ◽

Patient Characteristics ◽

Small Cell ◽

Small Cell Lung ◽

Lung Cancers ◽

And Migration ◽

Proliferation And Migration

Background Small-cell lung cancer (SCLC) accounts for approximately 15% to 20% of all lung cancers, and it is the leading cause of tumor-related deaths globally. This study explored the molecular mechanisms underlying the development of SCLC. Methods The correlations of phosphoinositide-dependent kinase-1 (PDPK1), p-Akt, and Hedgehog expression with patient characteristics were analyzed using SCLC specimens, and their expression was measured in BEAS-2B cells (control) and the SCLC cell lines H82, H69, H446, H146, and H526. Transfection experiments were performed to inhibit or activate gene expression in cells. We then measured the proliferation and migration of H146 cells. Results PDPK1, p-Akt, and Hedgehog expression was significantly higher in SCLC tissues, and their expression was correlated with patient characteristics. p-Akt expression was significantly correlated with Hedgehog expression. In H146 cells, PDPK1 and p-Akt were significantly upregulated. Silencing of PDPK1 or Akt and inhibition of Hedgehog significantly inhibited the proliferation and migration of H146 cells. PDPK1 and Akt affected Hedgehog expression, but Hedgehog did not affect PDPK1 or p-Akt expression. Conclusions The interaction between the PDPK1–Akt pathway and the Hedgehog pathway influences the prognosis, growth, and migration of SCLC.

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