The role of extracellular matrix in small-cell lung cancer

Lung cancer is the most common fatal malignant disease in the western world, accounting for 42,000 deaths each year in the UK alone. Small-cell lung cancer (SCLC), accounts for 25% of all lung cancers. It is a particularly aggressive form of the disease, characterised by widespread metastases and the development of resistance to chemotherapy. Even with combination chemotherapy and radiotherapy treatments, the 5-year survival is only about 5%. We review recent insights into the mechanisms underlying the development of metastases and resistance to chemotherapeutic agents in SCLC, focusing on the role of the extracellular matrix (ECM). We discuss the regulation of the interactions between cells and the ECM and the effects of these interactions on cellular phenotypes, together with some of the new approaches for combating drug resistance and metastases in this disease.     

Functional role of DNA mismatch repair gene PMS2 in prostate cancer cells

DNA mismatch repair (MMR) enzymes act as proofreading complexes that maintains genomic integrity and MMR-deficient cells show an increased mutation rate. MMR has also been shown to influence cell signaling and the regulation of tumor development. MMR consists of various genes and includes post-meiotic segregation (PMS) 2 which is a vital component of mutL-alpha. In prostate, the functional role of this gene has never been reported and in this study, our aim was to investigate the effect of PMS2 on growth properties of prostate cancer (PCa) cells. Previous studies have shown PMS2 to be deficient in DU145 cells and this lack of expression was confirmed by Western blotting whereas normal prostatic PWR-1E and RWPE-1 cells expressed this gene. PMS2 effects on various growth properties of DU145 were then determined by creating stable gene transfectants. Interestingly, PMS2 caused decreased cell proliferation, migration, invasion, and in vivo growth; and increased apoptosis as compared to vector control. We further analyzed genes affected by PMS2 expression and observe the apoptosis-related TMS1 gene to be significantly upregulated whereas anti-apoptotic BCL2A1 was downregulated. These results demonstrate a functional role for PMS2 to protect against PCa progression by enhancing apoptosis of PCa cells.     

Voltage-dependent ion channels in small-cell lung cancer cells

Small-cell carcinoma of the lung is a highly lethal form of cancer associated with a wide variety of paraneoplastic syndromes. Using the patch-clamp technique, we have directly demonstrated the presence of voltage-gated K+, Na+, and Ca2+ channels in three cell lines of human small-cell carcinoma, NCI-H128, NCI-H69, and NCI-H146. Whole-cell currents were measured from the tumor cells held at -80 mV and depolarized to -60 to +120 mV. Outward K+ current (IK), which was found in every cell tested, reached 1.58 +/- 0.12 nA (mean +/- SE, n = 24 cells) for H128 cells and 2.14 +/- 0.18 nA (n = 41) for H69 cells in response to a test potential of +80 mV. Unlike H69 and H128 tumor cells, IK from H146 cells occasionally exhibited partial inactivation during the 60-ms pulse length and reached 0.94 +/- 0.15 nA (n = 18) in response to a +80 mV test potential. IK from each of the cell lines was significantly reduced by 4-aminopyridine and tetraethylammonium. The rapidly inactivating inward Na+ current (INa), recorded in H146 cells and about 30% of the H69 and H128 cells tested, demonstrated a peak amplitude of 58 +/- 6 pA (n = 11) at 0 mV and a reversal potential of 47 +/- 2 mV (n = 11). Externally applied tetrodotoxin quickly suppressed INa. For the H128 and H69 tumor cells, inward Ca2+ current (ICa), observed in about 25% of the cells exposed to 10 mM [Ca2+]o, peaked at 5.1 +/- 0.4 ms (n = 5) with an amplitude of 46 +/- 14 pA (n = 5) at +20 mV and partially inactivated over the 40-ms depolarization. In H128 cells exposed to isotonic Ba2+ (110 mM), inward currents with time courses similar to those of ICa were recorded. Nearly all H146 tumor cells demonstrated a significant inward Ca2+ current which peaked with an amplitude of 93 +/- 16 pA (n = 26) at +30 to +40 mV in the presence of 10 mM [Ca2+]o. Application of test potentials 2 s in duration revealed that H146 ICa inactivated in a voltage-dependent manner with a time constant on the order of seconds. Adjustment of the holding potential from -80 mV to -40 mV had no observable effect on the amplitude of the evoked current. These voltage-dependent ion channels may have integral roles in several small-cell carcinoma bioelectric phenomena, including secretion, resting membrane potential, and action potential generation.(ABSTRACT TRUNCATED AT 400 WORDS)     

The role of external beam radiotherapy in the treatment of small-cell lung cancer

External beam radiotherapy plays a significant role in the treatment of small cell lung cancer. In patients with limited stage disease (LD), thoracic irradiation improves locoregional tumor control, increases the percentage of patients achieving a complete response (CR), and produces significant increases in survival. As a result, combined modality therapy (chemotherapy/radiotherapy) is considered the treatment of choice in patients with LD. Radiotherapy plays a less significant role in extensive diseased patients, but nonetheless increases CR in the chest and has palliative benefit. Elective cranial irradiation decreases the development of central nervous system failure, thereby improving the quality of life of many patients. Its use, however, should be restricted to patients achieving CR to therapy and doses should be modest. Both whole-body and hemi-body irradiation have significant activity against the disease but should be considered strictly investigational.     

Emerging role of topotecan in first-line therapy of small-cell lung cancer

Topotecan, a novel topoisomerase I inhibitor, is an established treatment for patients with recurrent small-cell lung cancer (SCLC), with antitumor response rates of approximately 20% and median survival of approximately 32 weeks in patients with extensive-stage disease. Topotecan's comparable activity relative to other agents used in SCLC and its novel mechanism of action, noncumulative toxicity, and in vitro synergy with other active agents have provided the rationale for investigating topotecan in first-line therapy. Furthermore, topotecan penetrates the blood-brain barrier and is potentially useful for the relatively large subset of patients with SCLC and brain metastases. In early studies of topotecan in brain metastases, encouraging antitumor activity has been observed. In several feasibility and phase II studies of topotecan as single-agent therapy in patients with extensive- and limited-stage tumors and as part of novel first-line combination regimens, overall response rates have ranged from 42% to 100%. Complete responses of 3%-67% and partial responses of 33%-80% have been observed in first-line therapy. Furthermore, the median overall survival in patients receiving topotecan in first-line therapy has ranged from approximately 8 months (extensive-stage disease) to 20 months (limited-stage disease). The most frequent adverse events associated with topotecan-based regimens include grade 3/4 neutropenia and thrombocytopenia that often require the incorporation of growth factor support into the treatment regimen. Nonhematologic adverse events associated with topotecan-based combination regimens have been mild or primarily attributed to other agents in the combination. Alternative doses and schedules (3 consecutive days and weekly) are being explored because they appear to be associated with considerably less myelosuppression. Although several trials have established the feasibility and activity of topotecan in first-line therapy of patients with SCLC, randomized phase III studies with comparison to standard therapy will be required to confirm a potential role for this active agent and to determine the optimal dosing regimen.     

Radiotherapy in small-cell lung cancer

Radiotherapy is a critical component of multi-modality treatment of LS-SCLC and has an emerging role in ES-SCLC. Many of the recent advances in the management of SCLC have come by refining the role of radiotherapy in this disease. A significant amount of research is currently focused on the targeting of specific signaling cascades implicated in SCLC pathogenesis (eg Hedgehog, c-MET, insulin-like growth factor receptor 1 [IGFR-1R], mammalian target of rapamycin [mTOR], vascular endothelial growth factor [VEGF], and p53 and Bcl-2 pathways) and on other novel approaches to therapy including treatment with a novel oncolytic virus with tropism for neuroendocrine cells and CD56-targeted drug delivery. Clinical investigations of many of these therapies are ongoing, and the results may become available over the next several years.     

The role of mismatch repair in DNA damage-induced apoptosis

DNA mismatch repair plays a critical role in maintaining genomic integrity. Defects in human mismatch repair are the primary cause of certain types of cancer, including hereditary nonpolyposis colorectal cancer. In the past, the ability of mismatch repair proteins to correct DNA mismatches that occur during DNA replication, repair, and recombination was considered the primary mechanism by which it contributes to genomic stability. However, increasing evidence supports the idea that the mismatch repair system also contributes to genome stability by stimulating DNA damage-induced apoptosis as part of the cytotoxic response to physical and chemical agents. MutS/MutL homologues mediate the process of apoptosis by binding to DNA adducts and either provoking futile repair events or blocking steps in DNA metabolism (i.e., DNA replication and/or repair). This damage recognition step by mismatch repair (MMR) proteins stimulates a signaling cascade for apoptosis, resulting in activation of protein kinase(s) that phosphorylate p53 and/or the related protein p73. Activated p53 and p73 in turn transmit a signal to the apoptotic machinery to execute cell death. The goal of this commentary is to discuss the molecular mechanism(s) by which mismatch repair proteins stimulate apoptosis.     

Extensive-stage small-cell lung cancer

Extensive-stage small-cell lung cancer (ES-SCLC) continues to be a difficult management issue. While response rates to therapy are relatively high, durable responses are rare, and long-term survival rates are dismal. Although many attempts have been made to develop new therapies, cisplatin-based combination chemotherapy remains the mainstay in the management of these patients. In this review we highlight recent developments in the treatment and management of this malignancy, and discuss future prospects in treatment.     

Limited-disease small-cell lung cancer

Substantial improvements in treatment outcome for limited-disease small-cell lung cancer (LD SCLC) have been achieved in the last two decades owing to the introduction of chemotherapy (CHT) consisting of cisplatin and etoposide (PE), and the understanding that thoracic radiation therapy (TRT) is an essential component in improving treatment outcome. In addition, a recent metaanalysis confirmed the importance of prophylactic cranial irradiation (PCI) in general treatment plans for patients who show a complete response to treatment. However, numerous questions remain unanswered regarding this disease. While TRT/PE/PCI is considered to be the standard treatment in the majority of centers worldwide, the emergence of new and effective drugs (e.g., topoisomerase I inhibitors and paclitaxel) for the treatment of LD SCLC will likely affect therapy strategies in the near future. Important issues regarding optimal doses and fractionation regimens, as well as the timing of TRT, remain to be resolved. While most centers currently use b.i.d. fractionation as a result of the Intergroup findings, high-dose standard TRT may also be beneficial. TRT volumes are also considered an important issue, since they likely relate to the incidence of both local failure and toxicity. Finally, the optimization of PCI (total dose, fractionation regimen, and timing) is already under way. The value of surgery is limited to peripheral tumors and poorly responding cancer, and to confirm histology or improve local control and survival.     

Progress in treatment of small-cell lung cancer: role of CPT-11

Small-cell lung cancer (SCLC) accounts for approximately 15% of all cases of lung cancer and is a particularly aggressive form of lung cancer characterised by a poor prognosis, rapid tumour growth, and early metastasis. Roughly, two-thirds of patients with SCLC present with extensive disease (ED) and one-third with limited disease (LD). Combination chemotherapy is the most effective treatment modality for SCLC, and several new agents, including carboplatin, ifosfamide, taxans, and topotecan, have been demonstrated to be active; however, there are no data on the survival benefit of these drugs. A CPT-11+ cisplatin regimen has shown improvement in overall survival over the global gold standard regimen, etoposide + cisplatin (Japanese Clinical Oncology Group: JCOG 9511), and three confirmatory randomised controlled trials are in progress to determine the reproducibility of the JCOG 9511 study. JCOG is evaluating the role of CPT-11 and a new triplet regimen containing CPT-11 in limited-stage SCLC. Strategies and the current protocols of the JCOG are presented and discussed. In the future, it will be essential to evaluate molecular target-based drugs for LD and ED SCLC with new standard combination chemotherapy regimens that include CPT-11.     

The role of DNA repair pathways in cisplatin resistant lung cancer

Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.     

The role of stem cells in airway repair:implications for the origins of lung cancer

Lung cancer is the leading cause of cancer-related deaths worldwide.Recently,advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properties may have in lung tumorigenesis.Much of this research has focused on the use of the airway repair model to study response to injury.In this review,we discuss the primary evidence of the role that cancer stem cells play in lung cancer development.The implications of a stem cell origin of lung cancer are reviewed,and the importance of ongoing research to identify novel therapeutic and prognostic targets is reiterated.     

History of small-cell lung cancer

The history of small-cell lung cancer (SCLC) is one of the more fascinating stories of medicine, a story of hope and disappointment that characterizes it as 1 of the most elusive cancers. Its history can be divided into 3 intervals. The first interval encompassed the 30 years after the initial reports from Bernard in 1926 during which SCLC was characterized. The second interval, from the 1960s-1980s, introduced advances in staging and treatment of SCLC and the advent of chemotherapy and radiation therapy (RT) as the primary forms of therapy. The final interval covers the past 25 years, which is considered a dormant period, although there are some shimmers of hope from the emergence of several new active drugs that are currently undergoing clinical trials.     

Ultrastructure of small-cell lung cancer

The research was concerned with electron microscopic analysis of 34 lung tumors histologically identified as small cell lung cancer. It was shown that ultrastructural studies can reliably identify histologic pattern of small cell lung cancer. In most cases, this type of cancer was represented by one of the following histologic patterns: epidermoid, glandular or neuroendocrine, the latter being predominant. An ultrastructural classification of small cell lung cancer is not advisable until a clinico-morphological analysis has been carried out.