scholarly journals Neuronal mimicry generates an ecosystem critical for brain metastatic growth of SCLC

2021 ◽  
Author(s):  
Fangfei Qu ◽  
Siqi Cao ◽  
Wojciech Michno ◽  
Chioma J. Madubata ◽  
Alyssa Puno ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Patients ◽  
State Transition ◽  
Small Cell ◽  
Small Cell Lung ◽  
Metastatic Growth ◽  
A Cell ◽  
The Brain

Brain metastasis is a major cause of morbidity and mortality in cancer patients. Here we investigated mechanisms allowing small-cell lung cancer (SCLC) cells to grow in the brain. We show that SCLC cells undergo a cell state transition towards neuronal differentiation during tumor progression and metastasis, and that this neuronal mimicry is critical for SCLC growth in the brain. Mechanistically, SCLC cells re-activate astrocytes, which in turn promote SCLC growth by secreting neuronal pro-survival factors such as SERPINE1. We further identify Reelin, a molecule important in brain development, as a factor secreted by SCLC cells to recruit astrocytes to brain metastases in mice. This recruitment of astrocytes by SCLC was recapitulated in assembloids between SCLC aggregates and human cortical spheroids. Thus, SCLC brain metastases grow by co-opting mechanisms involved in reciprocal neuron-astrocyte interactions during development. Targeting such developmental programs activated in this cancer ecosystem may help treat brain metastases.

Brain Metastases of Non–Small Cell Lung Cancer: Prognostic Factors in Patients with Surgical Resection

2017 ◽  
Vol 79 (02) ◽  
pp. 101-107 ◽  
Author(s):  
Aida Antuña ◽  
Carmen Sanchez ◽  
Vanesa Fernandez ◽  
Marco Vega
Keyword(s):  
Lung Cancer ◽  
Prognostic Factors ◽  
Survival Rate ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Surgical Resection ◽  
Survival Rates ◽  
Small Cell ◽  
Small Cell Lung ◽  
The Brain

Background and Study Aims Bronchogenic carcinoma is the cancer that most commonly metastasizes to the brain. The standard treatment schedule for these patients is still unclear, although recommendation level 1 class I advocates for surgical resection together with postoperative whole-brain radiotherapy for patients with good Karnofsky performance status (KPS). We performed a study to identify prognostic factors for the long-term survival of patients with brain metastases from non–small cell lung cancer (NSCLC). Patients This retrospective single-center study included 71 patients with brain metastases from NSCLC having undergone surgical metastasectomy between January 2002 and January 2015. Results The average age was 58.8 years. A total of 85.9% of the lesions were located in the supratentorial region, 61.9% of the lesions were < 3 cm, and 80.3% of cases were solitary brain metastases. Complete resection was achieved in 90.1% of patients. Clinical debut with motor involvement was associated with higher rates of incomplete surgical resection. Patients with motor deficits had a worse preoperative KPS. The preoperative KPS was > 70 in 74.6% of patients, and the postoperative KPS was > 70 in 85.9% of patients. Overall, 84.5% of the brain surgeries had no complications. Brain metastases were diagnosed as a synchronous presentation in 64.7% of patients.The average survival after brain surgery was 20.38 months. The survival rate was 66.2% at 6 months, 45.1% at 12 months, 22.5% at 24 months, 14.1% at 36 months, and 8.5% at 48 months. Patients < 55 years of age showed a higher survival rate at 12 months and 48 months. Patients > 70 years of age showed a higher mortality rate at 6 months. Complete surgical brain metastasis resection was associated with an increased survival at 6 months, and patients undergoing primary lung surgery had better survival rates at 48 months. A preoperative KPS > 70% improved the prognosis of patients at 6 and 24 months. Surgical complications reduced survival at 6 and 12 months. Conclusion Surgical resection may be beneficial for a given group of patients: a preoperative KPS > 70; age < 55 years, complete surgical brain metastasis resection, no surgical complications, patients with primary lung surgery, and complete radiotherapy treatment. We did not find any significant difference regarding further factors that probably affect survival rates such as size or number of metastases.

scholarly journals Bevacizumab suppresses the growth of established non-small-cell lung cancer brain metastases in a hematogenous brain metastasis model

2019 ◽  
Vol 37 (1) ◽  
pp. 199-207
Author(s):  
Chinami Masuda ◽  
Masamichi Sugimoto ◽  
Daiko Wakita ◽  
Makoto Monnai ◽  
Chisako Ishimaru ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell Line ◽  
Small Cell Lung ◽  
The Brain

AbstractBrain metastases are common in patients with non-small-cell lung cancer (NSCLC). The efficacy of bevacizumab, an anti-vascular endothelial growth factor (VEGF) humanized antibody, has been demonstrated in patients with nonsquamous NSCLC. We established a transplantable NSCLC cell line (Nluc-H1915) that stably expresses NanoLuc® reporter and confirmed the correlation between total Nluc activity in tumor and tumor volume in vivo. SCID mice inoculated with these cells through the internal carotid artery formed reproducible brain metastases, in which human VEGF was detected. Next, after metastases were established in the model mice (15–17 days), they were intraperitoneally administered weekly doses of human immunoglobulin G (HuIgG) or bevacizumab. Nluc activity in the brain was significantly lower in bevacizumab-treated mice than in HuIgG-treated mice. Additionally, bevacizumab concentration in the brain was higher in mice with brain metastasis than in normal mice, and bevacizumab was primarily observed in brain metastasis lesions. The microvessel density in brain metastasis was lower in bevacizumab-treated mice than in HuIgG-treated mice. We believe bevacizumab’s anti-proliferative effect on brain metastasis is due to anti-angiogenic activity achieved by its penetration into brain metastases; this suggests that a bevacizumab-containing regimen may be a promising treatment option for patients with NSCLC brain metastasis.

Radiosurgery for patients with recurrent small cell lung carcinoma metastatic to the brain: outcomes and prognostic factors

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 247-254 ◽  
Author(s):  
Jason Sheehan ◽  
Douglas Kondziolka ◽  
John Flickinger ◽  
L. Dade Lunsford
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Content Type ◽  
The Brain ◽  
Fine Print

Object. Lung carcinoma is the leading cause of death from cancer. More than 50% of those with small cell lung cancer develop a brain metastasis. Corticosteroid agents, radiotherapy, and resection have been the mainstays of treatment. Nonetheless, median survival for patients with small cell lung carcinoma metastasis is approximately 4 to 5 months after cranial irradiation. In this study the authors examine the efficacy of gamma knife surgery for treating recurrent small cell lung carcinoma metastases to the brain following tumor growth in patients who have previously undergone radiation therapy, and they evaluate factors affecting survival. Methods. A retrospective review of 27 patients (47 recurrent small cell lung cancer brain metastases) undergoing radiosurgery was performed. Clinical and radiographic data obtained during a 14-year treatment period were collected. Multivariate analysis was utilized to determine significant prognostic factors influencing survival. The overall median survival was 18 months after the diagnosis of brain metastases. In multivariate analysis, factors significantly affecting survival included: 1) tumor volume (p = 0.0042); 2) preoperative Karnofsky Performance Scale score (p = 0.0035); and 3) time between initial lung cancer diagnosis and development of brain metastasis (p = 0.0127). Postradiosurgical imaging of the brain metastases revealed that 62% decreased, 19% remained stable, and 19% eventually increased in size. One patient later underwent a craniotomy and tumor resection for a tumor refractory to radiosurgery and radiation therapy. In three patients new brain metastases were demonstrating on follow-up imaging. Conclusions. Stereotactic radiosurgery for recurrent small cell lung carcinoma metastases provided effective local tumor control in the majority of patients. Early detection of brain metastases, aggressive treatment of systemic disease, and a therapeutic strategy including radiosurgery can extend survival.

scholarly journals A Case Report of Cefepime Encephalopathy in Small Cell Lung Cancer Patients with Brain Metastasis

2019 ◽  
Vol 108 (3) ◽  
pp. 568-574
Author(s):  
Hidetoshi Yanai ◽  
Kai Kawashima ◽  
Kai Yazaki ◽  
Takeshi Numata ◽  
Kyoko Ota ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Case Report ◽  
Brain Metastasis ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancer Patients

scholarly journals The structure of blood–tumor barrier and distribution of chemotherapeutic drugs in non-small cell lung cancer brain metastases

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ling-yun Ye ◽  
Li-xiang Sun ◽  
Xiu-hua Zhong ◽  
Xue-song Chen ◽  
Song Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Blood Vessels ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Chemotherapeutic Drugs ◽  
Small Cell Lung ◽  
Metastatic Lesions

Abstract Background Brain metastasis is an important cause of increased mortality in patients with non-small cell lung cancer (NSCLC). In brain metastasis, the blood–brain barrier (BBB) is frequently impaired, forming blood–tumor barrier (BTB). The efficacy of chemotherapy is usually very poor. However, the characteristics of BTB and the impacts of BTB on chemotherapeutic drug delivery remain unclear. The present study investigated the structure of BTB, as well as the distribution of routine clinical chemotherapeutic drugs in both brain and peripheral tumors. Methods Bioluminescent image was used to monitor the tumor load after intracranial injection of lung cancer Lewis cells in mice. The permeability of BBB and BTB was measured by fluorescent tracers of evans blue and fluorescein sodium. Transmission electron microscopy (TEM), immunohistochemistry and immunofluorescence were performed to analyze structural differences between BBB and BTB. The concentrations of chemotherapeutic drugs (gemcitabine, paclitaxel and pemetrexed) in tissues were assayed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Results Brain metastases exhibited increased BTB permeability compared with normal BBB detected by fluorescence tracers. TEM showed abnormal blood vessels, damaged endothelial cells, thick basement membranes, impaired intercellular endothelial tight junctions, as well as increased fenestrae and pinocytotic vesicles in metastatic lesions. Immunohistochemistry and immunofluorescence revealed that astrocytes were distributed surrounded the blood vessels both in normal brain and the tumor border, but no astrocytes were found in the inner metastatic lesions. By LC-MS/MS analysis, gemcitabine showed higher permeability in brain metastases. Conclusions Brain metastases of lung cancer disrupted the structure of BBB, and this disruption was heterogeneous. Chemotherapeutic drugs can cross the BTB of brain metastases of lung cancer but have difficulty crossing the normal BBB. Among the three commonly used chemotherapy drugs, gemcitabine has the highest distribution in brain metastases. The permeability of chemotherapeutic agents is related to their molecular weight and liposolubility.

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