Brain Metastasis from Small-Cell Lung Cancer with High Levels of Placental Growth Factor

Background/Aims: Neovascularization and invasion coordinate cancer metastases in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms are poorly understood. Recently, a substantial role of placental growth factor (PLGF) in cancer cell invasion has been acknowledged in several types of cancer, whereas a possible involvement of PLGF in the metastases of NSCLC has not been studied. Methods: Here, we analyzed the levels of PLGF and matrix metalloproteinase 9 (MMP9) in NSCLC specimens. We modified either PLGF or MMP9 levels in a NSCLC cell line A549, and examined the effects on the levels of MMP9 and PLGF. The cell invasiveness was quantified in a transwell cell migration assay. Pathway inhibitors were applied to determine the molecular mechanisms underlying the control of MMP9 by PLGF. Results: We found that PLGF and MMP9 levels both significantly increased in the NSCLC specimens and were strongly correlated. Overexpression of PLGF in NSCLC cells increased the levels of MMP9 and cell invasiveness, while inhibition of PLGF in NSCLC cells decreased the levels of MMP9 and cell invasiveness. However, modification of MMP9 levels in NSCLC cells did not alter the levels of PLGF. These data suggest that PLGF may regulate MMP9 in NSCLC cells, but not vice versa. Moreover, inhibition of MMP9 in PLGF-overexpressing NSCLC cells abolished the effects of PLGF on cell invasiveness, suggesting that PLGF increases cell invasion via MMP9. Furthermore, suppression of MAPK-p38, but not suppression of either MAPK-p42/p44, or PI3k, or JNK signaling, substantially abolished the effect of PLGF on MMP9, suggesting that PLGF may activate MMP9 via MAPK-p38 signaling pathway. Conclusion: PLGF-stimulated cancer invasion may be mediated through its effects on MMP9 activation in NSCLC cells.

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Abstract 2357: Prognostic value of placental growth factor expression in patients with metastatic or recurrent non-small cell lung cancer.

10.1158/1538-7445.am2013-2357 ◽

2013 ◽

Author(s):

Jung Hoon Kim ◽

Tae Jung Kim ◽

Kyu Sang Lee ◽

Yun Hwa Jung ◽

In Sook Woo ◽

...

Keyword(s):

Lung Cancer ◽

Growth Factor ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Prognostic Value ◽

Small Cell ◽

Placental Growth Factor ◽

Small Cell Lung ◽

Factor Expression ◽

Growth Factor Expression

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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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MMP9 activation triggered by epidermal growth factor induced FoxO1 nuclear exclusion in non-small cell lung cancer

Tumor Biology ◽

10.1007/s13277-014-1850-z ◽

2014 ◽

Vol 35 (7) ◽

pp. 6673-6678 ◽

Cited By ~ 45

Author(s):

Jun Pei ◽

Yuqing Lou ◽

Runbo Zhong ◽

Baohui Han

Keyword(s):

Lung Cancer ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Nuclear Exclusion ◽

Epidermal Growth ◽

Mmp9 Activation

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Resection of a solitary brain metastasis in a patient with small cell lung cancer—Long-term survival

European Journal of Cancer ◽

10.1016/0959-8049(94)00491-m ◽

1995 ◽

Vol 31 (3) ◽

pp. 419 ◽

Cited By ~ 9

Author(s):

R.P. Abratt ◽

M. de Groot ◽

P.A. Willcox

Keyword(s):

Lung Cancer ◽

Brain Metastasis ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Term Survival ◽

Solitary Brain Metastasis ◽

Long Term Survival

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Phase II, Multicenter, Uncontrolled Trial of Single-Agent Sorafenib in Patients With Relapsed or Refractory, Advanced Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.0541 ◽

2009 ◽

Vol 27 (26) ◽

pp. 4274-4280 ◽

Cited By ~ 144

Author(s):

George R. Blumenschein ◽

Ulrich Gatzemeier ◽

Frank Fossella ◽

David J. Stewart ◽

Lisa Cupit ◽

...

Keyword(s):

Lung Cancer ◽

Growth Factor ◽

Small Cell Lung Cancer ◽

Phase Ii ◽

Cell Lung Cancer ◽

Advanced Nsclc ◽

Growth Factor Receptor ◽

Small Cell ◽

Continuous Treatment ◽

Small Cell Lung

PurposeSorafenib is an oral multikinase inhibitor that targets the Ras/Raf/MEK/ERK mitogenic signaling pathway and the angiogenic receptor tyrosine kinases, vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor β. We evaluated the antitumor response and tolerability of sorafenib in patients with relapsed or refractory, advanced non–small-cell lung cancer (NSCLC), most of whom had received prior platinum-based chemotherapy.Patients and MethodsThis was a phase II, single-arm, multicenter study. Patients with relapsed or refractory advanced NSCLC received sorafenib 400 mg orally twice daily until tumor progression or an unacceptable drug-related toxicity occurred. The primary objective was to measure response rate.ResultsOf 54 patients enrolled, 52 received sorafenib. The predominant histologies were adenocarcinoma (54%) and squamous cell carcinoma (31%). No complete or partial responses were observed. Stable disease (SD) was achieved in 30 (59%) of the 51 patients who were evaluable for efficacy. Four patients with SD developed tumor cavitation. Median progression-free survival (PFS) was 2.7 months, and median overall survival was 6.7 months. Patients with SD had a median PFS of 5.5 months. Major grades 3 to 4, treatment-related toxicities included hand-foot skin reaction (10%), hypertension (4%), fatigue (2%), and diarrhea (2%). Nine patients died within a 30-day period after discontinuing sorafenib, and one patient experienced pulmonary hemorrhage that was considered drug related.ConclusionContinuous treatment with sorafenib 400 mg twice daily was associated with disease stabilization in patients with advanced NSCLC. The broad activity of sorafenib and its acceptable toxicity profile suggest that additional investigation of sorafenib as therapy for patients with NSCLC is warranted.

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