Profilin 2 promotes growth, metastasis, and angiogenesis of small cell lung cancer through cancer-derived exosomes.

Small cell lung cancer (SCLC) is highly aggressive and prone to hypervascular metastases. Recently, we found profilin 2 (PFN2) expression in SCLC but not in normal tissues. Furthermore, PFN2 expression had been shown to promote angiogenesis through exosomes. However, it remains unclear whether PFN2 contributes to the progression and metastasis of SCLC through angiogenesis. We report here that overexpression (OE) of PFN2 increased, whereas its knockdown (KD) decreased the proliferation, migration, and invasion of SCLC cell H446. The exosomes from OE-H446 (SCLC-OE-exo) exhibited similar effects on H446 properties. Culturing of endothelial cells (ECs) in SCLC-OE conditioned medium (CM) or SCLC-OE-exo increased the migration and tube formation ability of ECs, whereas SCLC-KD-CM and SCLC-KD-exo had inhibitory effects. Interestingly, both SCLC- and EC-derived exosomes were internalized in H446 more rapidly than in ECs. More importantly, OE-PFN2 dramatically elevated SCLC growth and vasculature formation as well as lung metastasis in tumor xenograft models. Finally, we found that PFN2 activated Smad2/3 in H446 and pERK in ECs, respectively. Taken together, our study revealed the role of PFN2 in SCLC development and metastasis, as well as tumor angiogenesis through exosomes, providing a new molecular target for SCLC treatment.

Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is a highly malignant type of lung cancer with no effective second-line chemotherapy drugs. Arsenic trioxide (As2O3) was reported to exert antiangiogenesis activities against lung cancer and induce poor development of vessel structures, similar to the effect observed following the blockade of Notch signaling. However, there are no direct evidences on the inhibitory effects of As2O3 on tumor growth and angiogenesis via blockade of Notch signaling in SCLC. Here, we found that As2O3 significantly inhibited the tumor growth and angiogenesis in SCLC and reduced the microvessel density. As2O3 disturbed the morphological development of tumor vessels and downregulated the protein levels of delta-like canonical Notch ligand 4 (Dll4), Notch1, and Hes1 in vivo. DAPT, a Notch signaling inhibitor, exerted similar effects in SCLC. We found that both As2O3 treatment and Notch1 expression knockdown resulted in the interruption of tube formation by human umbilical vein endothelial cells (HUVECs) on Matrigel. As2O3 had no effects on Dll4 level in HUVECs but significantly inhibited the expression of Notch1 and its downstream gene Hes1 regardless of Dll4 overexpression or Notch1 knockdown. These findings suggest that the antitumor activity of As2O3 in SCLC was mediated via its antiangiogenic effect through the blockade of Notch signaling, probably owing to Notch1 targeting.

Radiotherapy and chemotherapy change vessel tree geometry and metastatic spread in a small cell lung cancer xenograft mouse tumor model.

BACKGROUND: Tumor vasculature is critical for tumor growth, formation of distant metastases and efficiency of radio- and chemotherapy treatments. However, how the vasculature itself is affected during cancer treatment regarding to the metastatic behavior has not been thoroughly investigated. Therefore, the aim of this study was to analyze the influence of hypofractionated radiotherapy and cisplatin chemotherapy on vessel tree geometry and metastasis formation in a small cell lung cancer xenograft mouse tumor model to investigate the spread of malignant cells during different treatments modalities. METHODS: The biological data gained during these experiments were fed into our previously developed computer model "Cancer and Treatment Simulation Tool" (CaTSiT) to model the growth of the primary tumor, its metastatic deposit and also the influence on different therapies. Furthermore, we performed quantitative histology analyses to verify our predictions in xenograft mouse tumor model. RESULTS: According to the computer simulation the number of cells engrafting must vary considerably to explain the different weights of the primary tumor at the end of the experiment. Once a primary tumor is established, the fractal dimension of its vasculature correlates with the tumor size. Furthermore, the fractal dimension of the tumor vasculature changes during treatment, indicating that the therapy affects the blood vessels' geometry. We corroborated these findings with a quantitative histological analysis showing that the blood vessel density is depleted during radiotherapy and cisplatin chemotherapy. The CaTSiT computer model reveals that chemotherapy influences the tumor's therapeutic susceptibility and its metastatic spreading behavior. CONCLUSION: Using a system biological approach in combination with xenograft models and computer simulations revealed that the usage of chemotherapy and radiation therapy determines the spreading behavior by changing the blood vessel geometry of the primary tumor.

CD13 as target for tissue factor induced tumor vascular infarction in small cell lung cancer.

OBJECTIVES: Zinc-binding protease aminopeptidase N (CD13) is expressed on tumor vascular cells and tumor cells. It represents a potential candidate for molecular targeted therapy, e.g. employing truncated tissue factor (tTF)-NGR, which can bind CD13 and thereby induce tumor vascular infarction. We performed a comprehensive analysis of CD13 expression in a clinically well characterized cohort of patients with small cell lung cancer (SCLC) to evaluate its potential use for targeted therapies in this disease. MATERIAL AND METHODS: CD13 expression was analyzed immunohistochemically in 27 SCLC patients and correlated with clinical course and outcome. In CD-1 nude mice bearing human HTB119 SCLC xenotransplants, the systemic effects of the CD13-targeting fusion protein tTF-NGR on tumor growth were tested. RESULTS AND CONCLUSION: In 52% of the investigated SCLC tissue samples, CD13 was expressed in tumor stroma cells, while the tumor cells were negative for CD13. No prognostic effect was found in the investigated SCLC study collective with regard to overall survival (p>0.05). In CD-1 nude mice, xenografts of CD13 negative HTB119 SCLC cells showed CD13 expression in the intratumoral vascular and perivascular cells, and the systemic application of CD13-targeted tissue factor tTF-NGR led to a significant reduction of tumor growth. We here present first data on the expression of CD13 in SCLC tumor samples. Our results strongly recommend the further investigation of tTF-NGR and other molecules targeted by NGR-peptides in SCLC patients. Considering the differential expression of CD13 in SCLC samples pre-therapeutic CD13 analysis is proposed for testing as investigational predictive biomarker for patient selection.

Correlation of iodine uptake and perfusion parameters between dual-energy CT imaging and first-pass dual-input perfusion CT in lung cancer.

To investigate the potential relationship between perfusion parameters from first-pass dual-input perfusion computed tomography (DI-PCT) and iodine uptake levels estimated from dual-energy CT (DE-CT).The pre-experimental part of this study included a dynamic DE-CT protocol in 15 patients to evaluate peak arterial enhancement of lung cancer based on time-attenuation curves, and the scan time of DE-CT was determined. In the prospective part of the study, 28 lung cancer patients underwent whole-volume perfusion CT and single-source DE-CT using 320-row CT. Pulmonary flow (PF, mL/min/100 mL), aortic flow (AF, mL/min/100 mL), and a perfusion index (PI = PF/[PF + AF]) were automatically generated by in-house commercial software using the dual-input maximum slope method for DI-PCT. For the dual-energy CT data, iodine uptake was estimated by the difference (λ) and the slope (λHU). λ was defined as the difference of CT values between 40 and 70 KeV monochromatic images in lung lesions. λHU was calculated by the following equation: λHU = |λ/(70 - 40)|. The DI-PCT and DE-CT parameters were analyzed by Pearson/Spearman correlation analysis, respectively.All subjects were pathologically proved as lung cancer patients (including 16 squamous cell carcinoma, 8 adenocarcinoma, and 4 small cell lung cancer) by surgery or CT-guided biopsy. Interobserver reproducibility in DI-PCT (PF, AF, PI) and DE-CT (λ, λHU) were relatively good to excellent (intraclass correlation coefficient [ICC]Inter = 0.8726-0.9255, ICCInter = 0.8179-0.8842; ICCInter = 0.8881-0.9177, ICCInter = 0.9820-0.9970, ICCInter = 0.9780-0.9971, respectively). Correlation coefficient between λ and AF, and PF were as follows: 0.589 (P < .01) and 0.383 (P < .05). Correlation coefficient between λHU and AF, and PF were as follows: 0.564 (P < .01) and 0.388 (P < .05).Both the single-source DE-CT and dual-input CT perfusion analysis method can be applied to assess blood supply of lung cancer patients. Preliminary results demonstrated that the iodine uptake relevant parameters derived from DE-CT significantly correlated with perfusion parameters derived from DI-PCT.

[Advances in the Treatment of Relapsed Small Cell Lung Cancer].

Small cell lung cancer (SCLC) is a highly malignant tumor. The initial treatment of radiotherapy and chemotherapy are more sensitive, high remission rate, but susceptible to drug resistance and relapse after treatment. Although the treatment of lung cancer has undergone enormous changes in recent years, treatment for relapsed SCLC is still a difficult problem in clinical field. In view of the serious resistance of recurrent SCLC to the existing chemotherapeutic drugs, the research on recurrent SCLC around the world is focused on the clinical trial of new drug development, optimization of chemotherapy regimen and target drug development. This paper summarize and estimate studies and literature reports of chemotherapy and precision therapy for relapsed SCLC, hopefully it could help clinicians treat relapsed SCLC and give us clinical research direction for relapsed SCLC in the future.

Vasculogenic mimicry in small cell lung cancer.

Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) and cytokeratins consistent with vasculogenic mimicry (VM), a process whereby tumour cells form 'endothelial-like' vessels. Single-cell genomic analysis reveals characteristic SCLC genomic changes in both VE-cadherin-positive and -negative CTCs. Higher levels of VM are associated with worse overall survival in 41 limited-stage patients' biopsies (P<0.025). VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin. VE-cadherin is required for VM in NCI-H446 SCLC xenografts, where VM decreases tumour latency and, despite increased cisplatin intra-tumour delivery, decreases cisplatin efficacy. The functional significance of VM in SCLC suggests VM regulation may provide new targets for therapeutic intervention.

Hyperthermia induced HIF-1a expression of lung cancer through AKT and ERK signaling pathways.

BACKGROUND: Hyperthermia is a promising treatment for human lung cancer, but recurrence of the primary lesion is common, as the residual tumor becomes adapted to heat treatment and growth is induced by hypoxia-triggered HIF-1a expression. Here, we explored the effects of hyperthermia on HIF-1a expression, proliferation, and lung cancer angiogenesis. METHODS: Human NSCLC NCI-H1650 and SCLC NCI-H446 cell lines were used to examine cell viability, apoptosis, and HIF-1a expression level under a gradient of thermal conditions (37, 42 and 47 °C for 40 min). The 47 °C heat-adapted NCI-H1650 and NCI-H446 sublines (also called NCI-H1650-b and NCI-H446-b cells) had enhanced viability and HIF-1a expression levels compared to the parental and 42 °C heat-adapted cells and were thus used for subsequent research. Concentration gradients of wortmannin and PD98095 were used to inhibit AKT and ERK expression, respectively in the NSCLC NCI-H1650-b and SCLC NCI-H446-b cell lines, and cell growth curves were drawn. Western blots were used to detect the expression of HIF-1a, extracellular signal-regulated kinase (ERK), protein kinase B (AKT), phospho-ERK, and phospho-AKT. We established a subcutaneous transplantation tumor model with wortmannin and PD98095 intervention. Immunohistochemistry was used to detect the expression of HIF-1a and the vascular specific marker CD34, and tumor growth curves were drawn. RESULTS: Following hyperthermia treatment, HIF-1a expression in 47 °C heat-adapted NSCLC and SCLC cell lines was regulated by the AKT pathway. However, HIF-1a expression was also regulated by the ERK pathway in NSCLCs, while SCLCs did not exhibit changes in ERK. These biological behaviors are governed by signaling pathway protein phosphorylation. Furthermore, inhibiting the AKT pathway can suppress the proliferation and angiogenesis potential of both 47 °C heat-adapted NSCLCs and SCLCs, but inhibiting the ERK pathway only affects SCLCs. CONCLUSION: Our study suggests that following hyperthermia, the proliferation and angiogenesis potential of residual NSCLCs and SCLCs is induced by HIF-1a. However, HIF-1a expression in NSCLCs is regulated by both the AKT and ERK signaling pathway, but HIF-1a expression in SCLCs is regulated only by the AKT signaling pathway. This study sheds light on the molecular regulatory mechanisms of lung cancer recurrence following hyperthermia treatment.

Angiogenesis of lung cancer utilizes existing blood vessels rather than developing new vessels using signals from carcinogenesis.

Cancer cells metastasize via angiogenesis and are a long-standing therapeutic target in malignant tumors. Vascular endothelial growth factor (VEGF) antibodies have been developed for clinical use, with limited benefits. Therefore, identifying the underlying mechanisms of angiogenesis regarding whether tumor vessels are derived from cancer cells or blood vessels in existence, is highly anticipated. Recently, epidermal growth factor receptor (EGFR) antibodies were utilized to detect cancer cells with somatic mutations of EGFR. The concordance rate is high for detection between immunohistochemical staining and polymerase chain reaction (PCR)-based methods. We hypothesized that endothelial cells exhibiting lymphatic and venous tumor invasiveness will be immunoreactive if new blood vessels are derived from the lung cancer itself, because EGFR mutations occur at a relatively early phase in carcinogenesis. We examined endothelial cells with EGFR mutations exhibiting lymphatic and venous tumor invasiveness using these antibodies. Tumor samples were obtained from 848 consecutive patients with lung cancer. Among 153 of 595 adenocarcinomas with EGFR-sensitive mutations, the number of lymphatic and venous invasive tumors was 35 and 19, respectively. Consequently, 12 available tumor specimens (five specimens for delE746-A750 and seven specimens for L858R) with both factors were evaluated. The main cancer cells were highly immunoreactive; however, no obvious lesions were detected with endothelial cells exhibiting lymphatic or venous invasiveness. Therefore, the angiogenesis of lung cancer seems to utilize blood vessels in existence, rather than create new vessels using signals from carcinogenesis.

Inhibition of SUR1 decreases the vascular permeability of cerebral metastases.

Inhibition of sulfonylurea receptor 1 (SUR1) by glyburide has been shown to decrease edema after subarachnoid hemorrhage. We investigated if inhibiting SUR1 reduces cerebral edema due to metastases, the most common brain tumor, and explored the putative association of SUR1 and the endothelial tight junction protein, zona occludens-1 (ZO-1). Nude rats were intracerebrally implanted with small cell lung carcinoma (SCLC) LX1 or A2058 melanoma cells (n = 36). Rats were administered vehicle, glyburide (4.8 µg twice, orally), or dexamethasone (0.35 mg, intravenous). Blood-tumor barrier (BTB) permeability (K (trans)) was evaluated before and after treatment using dynamic contrast-enhanced magnetic resonance imaging. SUR1 and ZO-1 expression was evaluated using immunofluorescence and Western blots. In both models, SUR1 expression was significantly increased (P < .05) in tumors. In animals with SCLC, control mean K (trans) (percent change ± standard error) was 101.8 ± 36.6%, and both glyburide (-21.4 ± 14.2%, P < .01) and dexamethasone (-14.2 ± 13.1%, P < .01) decreased BTB permeability. In animals with melanoma, compared to controls (117.1 ± 43.4%), glyburide lowered BTB permeability increase (3.2 ± 15.4%, P < .05), while dexamethasone modestly lowered BTB permeability increase (63.1 ± 22.1%, P > .05). Both glyburide (P < .001) and dexamethasone (P < .01) decreased ZO-1 gap formation. By decreasing ZO-1 gaps, glyburide was at least as effective as dexamethasone at halting increased BTB permeability caused by SCLC and melanoma. Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema.

Enhanced tumor suppression by adenoviral PTEN gene therapy combined with cisplatin chemotherapy in small-cell lung cancer.

DNA-damaging anticancer drug cisplatin (cis-diamminedichloroplatinum) (DDP)-based chemotherapy is the mainstay and standard treatment for small-cell lung cancer (SCLC). However, frequent relapse and chemoresistance of SCLC remains a significant therapeutic hurdle. Tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) as a negative regulator of phosphoinositide 3-kinase/AKT survival pathway exhibits strong tumor-suppressive activities. A combination of chemotherapy and gene therapy (chemogene therapy) is a promising practice in cancer therapy. In this report, we examined the combined antitumor effect of adenovirus-mediated PTEN (AdVPTEN) gene therapy and DDP chemotherapy on PTEN-null NCI-H446 human SCLC cells in vitro and in vivo in athymic BALB/c nude mice. We demonstrated that AdVPTEN plus DDP enhanced growth suppression, cell-cycle G1 phase arrest and apoptosis in in vitro NCI-H446 tumor cells and in vivo NCI-H446 xenografted tumors subcutaneously inoculated in nude mice. Mechanistically, AdVPTEN plus DDP exerted an overlapping effect on upregulation of P53, P21, P27, Bax and Cleaved Caspase-3 as well as downregulation of Bcl-2 and survivin in in vitro and in vivo NCI-H446 tumor cells. Moreover, AdVPTEN plus DDP additively reduced tumor vessel CD34 expression and microvessel density in vivo. The enhanced therapeutic efficacy elicited by AdVPTEN plus DDP was closely associated with additive induction of G1 phase arrest and apoptosis via substantially modulating cell-cycle regulation molecules and activating intrinsic apoptotic pathway through P53 restoration, and overlapping inhibition of tumor angiogenesis. Thus, our results indicated that AdVPTEN combined with DDP may be a novel and effective chemogene therapy modality for human SCLC.

Relation between vascular patterns visualized by Narrow Band Imaging (NBI) videobronchoscopy and histological type of lung cancer.

Narrow Band Imaging (NBI) videobronchoscopy is a new technique for visualization of microvascular changes in bronchial mucosa. The primary aim of this study was to evaluate relation between vascular patterns visualized by NBI and histology of lung cancer. We prospectively evaluated 65 patients with suspected lung cancer scheduled for bronchoscopy. NBI followed conventional WL videobronchoscopy. After identification of endoscopically visible tumor, NBI was used to determine predominant type of pathological vascular pattern (dotted, tortuous, abrupt-ending blood vessels-Shibuya descriptors). All the lesions were biopsied and histologically confirmed. There were 81.5 % male and 18.5 % female patients evaluated in the study. Lung cancer was confirmed in all patients; 63.1 % were diagnosed with squamous cell lung cancer (SCC), 24.6 % had adenocarcinoma, 9.2 % had small-cell (SCLC) and 3.1 % large-cell lung cancer (LC). Dotted blood vessels were significantly (p < 0.000) associated with adenocarcinoma, identified in 68.4 % adenocarcinoma and 31.6 % SCC. Tortuous blood vessels were identified in 72 % SCC, 8 % adenocarcinoma, 12 % SCLC and 8 % of LC. Tortuous blood vessels were significantly (p < 0.000) associated with SCC. Abrupt-ending vessels were identified in 81 % SCC, 14.3 % SCLC and 4.8 % adenocarcinoma and were significantly associated (p < 0.000) with SCC. Dotted visual pattern of blood vessels identified during NBI videobronchoscopy is highly suggesting adenocarcinoma histology of lung cancer. Tortuous and abrupt-ending blood vessels visualized under NBI videobronchoscopy significantly suggest squamous cell histology of lung cancer. Large-scale studies should be designed in order to determine true relation between visual appearance and histology in lung cancer.

Involvement of plasmin-mediated extracellular activation of progalanin in angiogenesis.

Progalanin is released from the small cell lung carcinoma line SBC-3A and converted to its active form by plasmin. To elucidate the role of progalanin activation in the extracellular compartment, matrix metalloproteinase (MMP) activity was studied in SBC-3A cells treated with progalanin siRNA, and angiogenesis was measured in tumor tissue originating from SBC-3A cell transplantation into mice. Progalanin siRNA caused downregulation of progalanin expression for approximately 8 days. MMP activity and angiogenesis were reduced in tumors induced by transplantation of progalanin siRNA-treated SBC-3A cells. In contrast, MMP-9 and MMP-2 activity and angiogenesis increased in tumors originating from progalanin siRNA-treated SBC-3A cells in the presence of galanin and progalanin. Furthermore, injection of tranexamic acid, a plasmin inhibitor, more markedly reduced MMP-9 and MMP-2 activity and angiogenesis in tumors originating from progalanin siRNA-treated SBC-3A cells and in tumor tissue originating from progalanin siRNA-treated SBC-3A cells in the presence of progalanin. The reduction of MMP-9 and MMP-2 activity with tranexamic acid was restored by galanin, but not by progalanin. Moreover, tranexamic acid reduced angiogenesis in control siRNA-treated SBC-3A cells. These results suggest that the activation of progalanin by plasmin in the extracellular compartment was involved in MMP-9 and MMP-2 activation and in angiogenesis in tumor tissue.

Emerging drugs for small cell lung cancer--an update.

INTRODUCTION: Small cell lung cancer (SCLC) is a biologically complex tumor whose medical treatment has remained largely unchanged over the last 30 years. The frustration for the invariably negative results reported in the early 2000s in clinical studies investigating new agents for this disease have contributed to the little interest shown by pharmaceutical industries in funding SCLC research. However, recent advances in the molecular understanding of the oncogenic mechanisms underlying SCLC have renewed the attraction for the clinical development of novel active drugs for the treatment of this challenging disease. AREAS COVERED: The authors briefly touch on the most promising agents under clinical development for the treatment of SCLC, either chemotherapeutic or targeted drugs. Relevant and recent (2 years) studies obtained through Pubmed literature research or released at International scientific meetings are presented. EXPERT OPINION: The data discussed herein provide evidence in support of the fact that only rationally designed clinical trials including relevant translational research may lead to successful results. Therefore, a thoughtful change in trial construction is crucial for the approval of new active drugs for this orphan disease.

HIF-1α effects on angiogenic potential in human small cell lung carcinoma.

BACKGROUND: Hypoxia-inducible factor-1 alpha (HIF-1α) maybe an important regulatory factor for angiogenesis of small cell lung cancer (SCLC). Our study aimed to investigate the effect of HIF-1α on angiogenic potential of SCLC including two points: One is the effect of HIF-1α on the angiogenesis of SCLC in vivo. The other is the regulation of angiogenic genes by HIF-1α in vitro and in vivo. METHODS: In vivo we used an alternative method to study the effect of HIF-1a on angiogenic potential of SCLC by buliding NCI-H446 cell transplantation tumor on the chick embryo chorioallantoic membrane (CAM) surface. In vitro we used microarray to screen out the angiogenic genes regulated by HIF-1a and tested their expression level in CAM transplantation tumor by RT-PCR and Western-blot analysis. RESULTS: In vivo angiogenic response surrounding the SCLC transplantation tumors in chick embryo chorioallantoic membrane (CAM) was promoted after exogenous HIF-1α transduction (p < 0.05). In vitro the changes of angiogenic genes expression induced by HIF-1α in NCI-H446 cells were analyzed by cDNA microarray experiments. HIF-1α upregulated the expression of angiogenic genes VEGF-A, TNFAIP6, PDGFC, FN1, MMP28, MMP14 to 6.76-, 6.69-, 2.26-, 2.31-, 4.39-, 2.97- fold respectively and glycolytic genes GLUT1, GLUT2 to2.98-, 3.74- fold respectively. In addition, the expression of these angiogenic factors were also upregulated by HIF-1α in the transplantion tumors in CAM as RT-PCR and Western-blot analysis indicated. CONCLUSIONS: These results indicated that HIF-1α may enhance the angiogenic potential of SCLC by regulating some angiogenic genes such as VEGF-A, MMP28 etc. Therefore, HIF-1α may be a potential target for the gene targeted therapy of SCLC.

Phase II trial of sunitinib maintenance therapy after platinum-based chemotherapy in patients with extensive-stage small cell lung cancer.

INTRODUCTION: The prognosis for patients with extensive-stage small cell lung cancer remains poor. This trial was designed to evaluate the efficacy and toxicity of maintenance sunitinib after platinum-etoposide chemotherapy. METHODS: Patients who demonstrated objective tumor response or stable disease after four cycles of platinum plus etoposide chemotherapy were eligible. Sunitinib was given at 50 mg daily for 4 weeks of a 6-week cycle until disease progression or unacceptable toxicity. The primary end point was 4-month progression-free survival (PFS) rate from initiation of sunitinib. RESULTS: Sixteen patients were enrolled. Responses to platinum-etoposide were complete response (CR)/partial response (PR)/stable disease (SD) = 3/11/2. The median number of weeks on sunitinib was 4 (range: 1.4-20). Reasons for sunitinib discontinuation were disease progression (50%), toxicity (31%), and patient request (19%). Median PFS from the start of sunitinib was 2.5 months (95% confidence interval [CI], 0.8-3.1). Further accrual would have failed to reach the target PFS rate, so the study was terminated. There were no objective responses to sunitinib, but four patients (25%) had disease stability for 15, 15, 17, and 20 weeks. Median PFS and overall survival from the start of chemotherapy were 6.2 months (95% CI, 4.1-6.5) and 8.2 months (95% CI, 6.2-14.7), respectively. Grade 3 to grade 4 toxicity included thrombocytopenia (25%), fatigue (19%), muscle weakness (13%), and hypothyroidism (6%). CONCLUSIONS: Sunitinib did not seem to maintain disease stability after response to chemotherapy. Sunitinib was discontinued in half of patients due to toxicity or request to stop therapy. Although disease stability with sunitinib was noted in four patients, this approach does not seem to warrant further clinical study.

Increased microcirculation in subepithelial invasion of lung cancer.

BACKGROUND AND OBJECTIVE: Mucosal irregularity and hypervascularity associated with primary lung cancer in large airways are observed by bronchoscopy. The aim of this study was to evaluate microcirculation at subepithelial invasion sites of lung cancer. METHODS AND PATIENTS: Between July 2001 and June 2007, 12 patients who had subepithelial invasion sites of lung cancer in the large airways (aged 52 to 74 years, 12 males) were enrolled into this study. They were 6 patients with adenocarcinoma, 4 patients with squamous cell carcinoma, and 2 patients with small cell carcinoma. We compared 12 control subjects without endobronchial abnormality (aged 51 to 83 years, 9 males and 3 females). The patients underwent conventional bronchoscopy and subsequent high magnification bronchovideoscopy with the conventional imaging and the narrow band imaging (NBI). For evaluating microcirculation of subepithelial invasion, hemoglobin index was calculated. RESULTS: In high magnification view, aberrant microvessels and/or irregular mucosal thickening were observed at subepithelial invasion sites of lung cancer. Irregularly enlarged microvessels were increased and formed an aberrant microvessel network on the surface of irregular mucosa. The diameter of aberrant microvessels was significantly increased compared to normal microvessels. By switching to NBI, the aberrant microvessels were more clearly visualized. The levels of hemoglobin index were significantly higher in subepithelial invasion sites of lung cancer compared to normal mucosa. CONCLUSION: In subepithelial invasion of lung cancer, aberrant microvessels are thought to be characteristic and subepithelial microcirculation may be increased.

Endoglin (CD105) expression and angiogenesis status in small cell lung cancer.

It is well established that angiogenesis is crucial for tumor development and progression. Among the angiogenesis immunomarkers defined to date, endoglin (CD105) has been shown to be a useful marker of angiogenesis. To investigate the degree of angiogenesis status in small cell lung cancer (SCLC) tissue, we assessed 35 cases of SCLC at autopsy using immunohistochemical staining of CD31 and CD105. The intratumoral area, peritumoral area, and background pulmonary alveoli were then observed under low magnification, and the microvessel density (MVD) for each area was determined. The MVD-CD31 was the highest in the background alveoli, followed by the intratumoral and peritumoral areas. The MVD-CD105 was highest in the intratumoral area, followed by the peritumoral area and the background lung. The ratio of CD105/CD31 revealed that almost 78% of the intratumoral area, 63% of the peritumoral area, and 4.6% of the background lung alveoli were newly formed and expressed CD105. This result indicated that SCLC is predominantly supported by newly formed vessels that are generated by CD105-mediated angiogenesis. These findings suggest that anti-angiogenic therapy, especially CD105-targeting, may prove an effective form of SCLC treatment.

[Molecular targeted therapies in small-cell lung cancer]. / Thérapies moléculaires ciblées dans le cancer du poumon à petites cellules.

Small-cell lung cancers (SCLC) are aggressive malignancies, however, characterized by high primary chemosensitivity. Unfortunately, for the vast majority of patients, relapse is the rule with emergence of secondary resistance mechanisms. In the era of molecular targeted therapies, characterization of a number of molecular abnormalities has encouraged implementation of several clinical trials. This literature review summarizes the various pharmacological approaches used in SCLC to improve survival in localized and extensive forms of the disease. Initial trials with molecular targeted therapies have not been able to improve clinical outcome compared to the standard etoposide-cisplatin chemotherapy regimen in extensive forms. However, new targets continue to be identified and many treatments are currently being assessed, including blockade of angiogenesis, signal transduction, cell cycle or induction of apoptosis.