Human cancers have been found to include transformed stem cells that may drive cancer progression to metastasis. Here, we report that metastatic colon cancer contains clonally derived tumor cells with all of the critical properties expected of stem cells, including self-renewal and the ability to differentiate into mature colon cells. Additionally, when injected into mice, these cells initiated tumors that closely resemble human cancer. Karyotype analyses of parental and clonally derived tumor cells expressed many consistent (clonal) along with unique chromosomal aberrations, suggesting the presence of chromosomal instability in the cancer stem cells. Thus, this new model for cancer origin and metastatic progression includes features of both the hierarchical model for cancerous stem cells and the stochastic model, driven by the observation of chromosomal instability. [Cancer Res 2008;68(17):6932-41]

Dendritic cells (DCs) are nature's best antigen-presenting cells. They possess attributes that allow them to effectively fulfill the requirements for priming/activating T cells and mediating tumor-specific immune responses. In this review, emphasis is placed on those aspects of DC biology that best illustrate their usefulness in immunotherapy of cancer. Culture, maturation, and polarization conditions for human DC are discussed, as are strategies for antigen-loading of DCs and for their delivery to patients with cancer. A concise recommendation for monitoring of DC-based vaccination trails is provided.

Paclitaxel induces apoptosis in lung cancer cell lines, as assessed by a consistent increase in caspase-3 activity, DNA laddering, and characteristic morphologic changes. Paclitaxel-induced apoptosis in human lung cancer cells is associated with caspase-3 activation but is not Fas dependent.

Endothelin-1 (ET-1), a potent fibroblast/smooth muscle cells mitogen, has been implicated in the pathogenesis of systemic sclerosis lung disease (SSc). Since monocytes and macrophages are thought to be activated in SSc, we hypothesized that alveolar macrophages (AM) and their precursors blood monocytes from patients with SSc produced more ET-1 than cells from healthy subjects. ET-1 and big ET-1 concentrations were measured in plasma, in bronchoalveolar lavage (BAL) fluids and in cell culture supernatants from monocytes and alveolar macrophages derived from 13 patients with definite SSc with lung involvement and from 10 control subjects. Plasma and BAL fluid ET-1 and big ET-1 levels were similar in both controls and patients with SSc. ET-1 and big ET-1 concentrations in unstimulated alveolar macrophage supernatants were similar in both groups. In contrast, LPS-stimulated alveolar macrophages from patients with SSc secreted higher amounts of ET-1 and big ET-1 than control subjects. ET-1 and big ET-1 concentrations in monocyte supernatants (either LPS-stimulated or not) were not different in patients and controls. These results show that AM from patients with SSc are hyperresponsive to LPS in vitro in terms of ET-1 and big ET-1 production and suggest that AM could participate in vivo in the overproduction of this potentially profibrotic mediator in patients with SSc.

In patients with stage IIB-III disease, adjuvant high-dose interferon-alpha2b has shown clinical benefit, although metastatic melanoma is currently without any known survival-prolonging therapy. Angiogenesis has been considered important in melanoma progression, and endostatin is an angiogenesis inhibitor with antitumor activity that has shown promising results in murine model systems, prompting investigation of a formulation of rh-Endostatin (EntreMed, Rockville, Maryland, USA) alone and with interferon in metastatic melanoma. Patients were randomly assigned to receive interferon alpha2b (Schering-Plough) 10 million units/m(2) subcutaneously three times a week plus rh-Endostatin 45 mg/m(2) subcutaneously every 12 h (arm A) vs. rh-Endostatin alone (arm B). Twenty-one patients (age range 31-77 years, median age 54, 12 men and nine women, 17 cutaneous, and four ocular melanomas) were enrolled. No antitumor responses were observed, and no significant differences were noted in time to progression or overall survival. Two patients had stable disease enduring more than 30 weeks on treatment. Serum endostatin levels increased significantly 4 weeks after treatment in both groups. Basic fibroblast growth factor levels in urine were significantly lower following treatment in patients on arm B (P=0.043). The percentage of circulating endothelial cells was increased in five evaluable patients 4 weeks after treatment. Low titer (

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Key words: lung cancer; paclitaxel; TRAIL; DR5; FasL; apoptosisLung cancer is among the most commonly occurring malignancies worldwide and accounts for 1,193,000 deaths in 1999. 1 In the United States, lung cancer is the leading cause of cancer death in men, and it is the second most frequent cancer in women after breast cancer. NSCLC accounts for about 75 to 80% of lung cancer cases and carries an overall 5-year survival of about 10 -15% despite recent advancements in multimodality therapies (chemoand radio-therapies). 2 Most of the widely used chemotherapeutic agents induce apoptosis in susceptible cancer cells. 3-5 However, after a first round of multimodality therapy in NSCLC cancer, the cells responsible for NSCLC reoccurrence are drug-resistant cancer cell clones. PA is an antineoplastic plant alkaloid derived from Taxus baccata, which is widely administered in the treatment of advanced and metastatic lung, esophagus, breast and ovarian carcinomas. PA induces a single agent response rate approaching 25% in the treatment of NSCLC 6 and increases survival up to 40 weeks. 7-9 PA induces cytotoxicity by stabilizing microtubules and inhibiting their disassembly, thereby arresting the cells in the G 2 -M phase of the cell cycle. 10 In addition, downstream intracellular events include DNA cleavage 11 and activation of several caspases. 12 Thus, PA kills tumor cells by inducing both cellular necrosis and apoptosis.Apoptosis is a distinct form of programmed cell death, which normally occurs in part to annihilate overgrowth of extra-numerous cells. Apoptosis is associated with chromatin condensation (karyorrhexis) and margination to the nuclear membrane, cytoskeletal alterations, membrane blebbing and formation of apoptotic bodies. 13 In addition, mitochondrial function is irreversibly impaired early in apoptosis. 14,15 One of the best-characterized pathways for initiation of apoptosis involves the binding of extracellular death signal proteins (TNF␣, Fas ligand, TRAIL and Apo-3) to their cognate cell surface receptors. 16,17 Fas receptor (CD95) is a TNF family member containing a death effector domain (DED). Fas ligand (FasL and CD95L) induces cross-linking and trimerization of Fas, causing apoptotic cell death in both lymphoid and non-lymphoid cells. 18 Downstream signaling from the Fas receptor is initiated by recruitment of proteins to form a death-inducing signaling complex (DISC). 19 The binding of FasL to Fas results in recruitment of FADD (Fas-Associating protein with Death Domain) that is then responsible for cleavage of the first of a series of cysteine-dependent aspartate-directed proteases called caspases. The first caspase to be activated is FLICE (FADD-like Interleukin-1 beta converting enzyme) or caspase-8, which results in a caspase cascade that culminates in cell death by apoptosis. 12,18,20 Caspase-3 activation is critical for successfully trigging apoptosis. 12 Fas is constitutively expressed on a variety of tumor cells 21-24 including human lung carcinoma cells. [25][26][27] Anticancer drugs used...

Type II alveolar epithelial cells (ATII cells) have been shown to play a key role in the regulation of the alveolar space. ATII cells synthesize and secrete surfactant, control the volume and composition of the epithelial lining fluid and proliferate and differentiate into type I alveolar epithelial cells after injury in order to maintain the integrity of the alveolar wall. Moreover, ATII cells are ideally located to have a role in modulating the activation or proliferation state of macrophages, fibroblasts or endothelial cells, because of the close proximity of the cell types in the alveolar space.The interactions between the alveolar epithelial cells and the other cells located in the alveoli are brought about by the secretion of mediators such as cytokines [1], but other mediators are probably involved in this phenomenon. Among these mediators, endothelin (ET)-1 a 21 amino acid peptide may play an important role. Indeed, beside its potent effect on the constriction of vascular and bronchial smooth muscle cells, ET-1 acts as a mitogen for different cell types, such as fibroblasts or smooth muscle cells [2]. ET-1 is also involved in the modulation of the inflammatory response through a direct effect on alveolar macrophages [3] or mastocytes [4].It has been shown that hyperplastic alveolar epithelial cells express preproendothelin-1 (preproET-1) messenger ribonucleic acid (mRNA) and immunoreactive ET (irET)-1 in the human fibrotic lung [5], although conflicting data exist [6]. Rat ATII cells in primary culture [7], and a cell line derived from rat ATII cells, have been shown to secrete ET-1 in vitro [8].Hypoxia has been identified as an important modulator of ET-1 production by endothelial cells. Hypoxia increases ET-1 production by human umbilical vein endothelial cells [9], but decreases ET-1 production by rat lung endothelial cells [10]. The effect of hypoxia on ET-1 production by rat ATII cells has never been evaluated, despite the fact that ATII cells are potential targets for hypoxia in the alveolar space both in physiological (high altitude) and pathological (e.g. lung parenchyma consolidation) conditions. Therefore, the aims of this study were: 1) to characterize the regulation of ET-1 production by rat ATII cells in primary culture under low oxygen tension; and 2) to evaluate the influence of nitric oxide on ET-1 production by rat ATII cells. Materials and methods ReagentsTissue culture media and foetal bovine serum were obtained from Gibco BRL Life Technologies (Cergy Pontoise, Hypoxia reduces endothelin production by rat alveolar type II cells in primary culture. B. Crestani, C. Odoux, C. Rolland, F. Moldovan, P. Cornillet, J. Fiet, M. Aubier. ©ERS Journals Ltd 1998. ABSTRACT: The purpose of the study was to describe endothelin (ET) production and to characterize the effect of hypoxia on preproendothelin-1 (preproET-1) messenger ribonucleic acid (mRNA) expression and ET secretion by rat type II pneumocytes in vitro.Rat type II pneumocytes were incubated in a sealed chamber containing a normoxic (21% ...