Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese?

Cancer of the bladder shows divergent clinical behaviour following diagnosis and it has been proposed that two major groups of tumours exist that develop via different molecular pathways. Low-grade, non-invasive papillary tumours recur frequently, but patients with these tumours do not often suffer progression of disease to muscle invasion. In contrast, tumours that are invading muscle at diagnosis are aggressive and associated with significant mortality. Molecular studies have identified distinct genetic, epigenetic and expression changes in these groups. However, it is not yet clear whether there is direct progression of low-grade superficial tumours to become invasive (a Jeckell and Hyde scenario) or whether in those patients who apparently progress from one form of the disease to the other, different tumour clones are involved and that the two tumour groups are mutually exclusive ('chalk and cheese'). If the latter is true, then attempts to identify molecular markers to predict progression of low-grade superficial bladder tumours may be fruitless. Similarly, it is not clear whether other subgroups of tumours exist that arise via different molecular pathways. There is now a large amount of molecular information about bladder cancer that facilitates examination of these possibilities. Some recent studies provide evidence for the existence of at least one further group of tumours, high-grade superficial papillary tumours, which may develop via a distinct molecular pathway. Patients with such tumours do show increased risk of disease progression and for these there may exist a real progression continuum from non-invasive to invasive. If this is the case, definition of the molecular signature of this pathway and improved understanding of the biological consequences of the events involved will be pivotal in disease management.     

Vav1: A Dr. Jekyll and Mr. Hyde protein – good for the hematopoietic system,bad for cancer

Many deregulated signal transducer proteins are involved in various cancers at numerous stages of tumor development. One of these, Vav1, is normally expressed exclusively in the hematopoietic system, where it functions as a specific GDP/GTP nucleotide exchange factor (GEF), strictly regulated by tyrosine phosphorylation. Vav was first identified in an NIH3T3 screen for oncogenes. Although the oncogenic form of Vav1 identified in the screen has not been detected in clinical human tumors, its wild-type form has recently been implicated in mammalian malignancies, including neuroblastoma, melanoma, pancreatic, lung and breast cancers, and B-cell chronic lymphocytic leukemia. In addition, it was recently identified as a mutated gene in human cancers of various origins. However, the activity and contribution to cancer of these Vav1 mutants is still unclear. This review addresses the physiological function of wild-type Vav1 and its activity as an oncogene in human cancer. It also discusses the novel mutations identified in Vav1 in various cancers and their potential contribution to cancer development as oncogenes or tumor suppressor genes.     

Autophagy in cancer: good, bad, or both?

Autophagy has been recognized as an important cellular process for at least 50 years; however, it is only with the recent identification of key regulators of autophagy (Atg genes) that we have begun a mechanistic exploration of its importance in cancer. Recent studies suggest that autophagy may be important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. However, the role of autophagy in these processes is complicated and may, depending on the circumstances, have diametrically opposite consequences for the tumor. In this article, we discuss recent discoveries regarding autophagy in cancer.     

Jekyll or Hyde: does Matrigel provide a more or less physiological environment in mammary repopulating assays?

In vivo transplantation is the current 'gold-standard' assay for evaluating mammary stem cell (MaSC) function. Matrigel, a reconstituted extracellular matrix derived from a mouse sarcoma line, is increasingly being utilized for mammary repopulating assays, although original studies were carried out in its absence. This matrix has also been shown to enhance tumor-initiating capacity. Whilst Matrigel increases the rate of engraftment by MaSCs, it also appears to promote progenitor activity that is distinct from bona fide stem cell activity. This caveat should be considered when interpreting mammary reconstitution assays that incorporate Matrigel, particularly when transplanting high cell numbers.     

Does "death receptor" signaling play a role in tumorigenesis and cancer therapy?

Physiological cell death, known as apoptosis, is an evolutionarily conserved process that is required for normal development and function of multicellular organisms. Abnormalities in cell death control are implicated as a cause or contributing factor in a range of diseases, including cancer, autoimmunity, and degenerative disorders. Importantly, the propensity of a cell to undergo apoptosis is one of the determinants of the sensitivity of tumor cells to antineoplastic therapy. Apoptosis can be triggered by stress-induced signals that arise from within the doomed cell or by signals that are elicited by binding of extracellular "death ligands" to their "death receptors." Cysteine proteases have been recognized as essential effectors of all pathways to apoptosis. Experiments with transgenic mice and gene knockout mice have shown that different caspases and their adaptor molecules are needed for "death receptor" signaling and apoptotic pathways elicited by cytokine withdrawal, DNA damage, or corticosteroids. These differences allow the pathways to be regulated by distinct inhibitors. It has been published that chemotherapeutic drugs and gamma-radiation induce apoptosis by "death ligand"-mediated activation of "death receptors," but this model has been challenged. Our review discusses this controversy in the light of current knowledge of the molecular control of apoptosis.     

Autophagy and apoptosis: rivals or mates?

Autophagy, a cellular process of "self-eating" by which intracellular components are degraded within the lysosome, is an evolutionarily conserved response to various stresses. Autophagy is associated with numerous patho-physiological conditions, and dysregulation of autophagy contributes to the pathogenesis of a variety of human diseases including cancer. Depending on context, activation of autophagy may promote either cell survival or death, two major events that determine pathological process of many illnesses. Importantly, the activity of autophagy is often associated with apoptosis, another critical cellular process determining cellular fate. A better understanding of biology of autophagy and its implication in human health and disorder, as well as the relationship between autophagy and apoptosis, has the potential of facilitating the development of autophagy -based therapeutic interventions for human diseases such as cancer.     

Adjuvant therapy in gastric and cardia cancer: should we irradiate?

PURPOSE OF REVIEW: The purpose of this review is to comment on the current status and the place of the (neo)adjuvant therapy of gastric cancer, and on the standardization of care in this setting. RECENT FINDINGS: The definition of optimal surgery remains controversial in gastric cancer. A recent review by the Dutch Gastric Cancer Group supports the so-called 'over-D1' extended lymphadenectomy, without pancreatectomy and splenectomy, as the optimal procedure, avoiding an increased postoperative mortality. The results from the phase III INT 116 trial should not definitively assign adjuvant chemoradiation as a robust standard of care, mainly due to the lack of optimal surgery in this trial. However, the concept of adjuvant chemoradiation will likely become more and more used, and will influence the design of future studies, reinforced by the incorporation of novel agents. If adjuvant chemotherapy failed to significantly increase survival, the use of perioperative chemotherapy (ECF regimen x 3 pre- and postoperative) was recently reported to improve survival, without affecting postoperative mortality and morbidity; mature results from this large phase III Medical Research Council Adjuvant Gastric Cancer Infusional Chemotherapy trial should be considered as an important step implementing neoadjuvant chemotherapy as a new standard of care. Neoadjuvant therapy of locally advanced tumors also offers an ideal setting to assess new combinations, including cytotoxics, biologics and conformational radiation, coupled with translational research. SUMMARY: Much remains to be done before anticipating an incontestable standard of care in gastric cancer, although the recent phase III trials indicate that multimodality therapy could impact on the prognosis of gastric cancer.     

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar^®), vinorelbine (Navelbine^®) and irinotecan (Campto^®), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20–30% and 1-year survival rates of 30–40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-α. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.     

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar), vinorelbine (Navelbine) and irinotecan (Campto), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20-30% and 1-year survival rates of 30-40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-alpha. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.