Cyclooxygenases and lipoxygenases in cancer

Cancer initiation and progression are multistep events that require cell proliferation, migration, extravasation to the blood or lymphatic vessels, arrest to the metastatic site, and ultimately secondary growth. Tumor cell functions at both primary or secondary sites are controlled by many different factors, including growth factors and their receptors, chemokines, nuclear receptors, cell-cell interactions, cell-matrix interactions, as well as oxygenated metabolites of arachidonic acid. The observation that cyclooxygenases and lipoxygenases and their arachidonic acid-derived eicosanoid products (prostanoids and HETEs) are expressed and produced by tumor cells, together with the finding that these enzymes can regulate cell growth, survival, migration, and invasion, has prompted investigators to analyze the roles of these enzymes in cancer progression. In this review, we focus on the contribution of cyclooxygenase- and lipoxygenase-derived eicosanoids to tumor cell function in vitro and in vivo and discuss hope and tribulations of targeting these enzymes for cancer prevention and treatment.     

Precision medicine for gastrointestinal cancer: Recent progress and future perspective

Gastrointestinal (GI) cancer has a high tumor incidence and mortality rate worldwide. Despite significant improvements in radiotherapy, chemotherapy, and targeted therapy for GI cancer over the last decade, GI cancer is characterized by high recurrence rates and a dismal prognosis. There is an urgent need for new diagnostic and therapeutic approaches. Recent technological advances and the accumulation of clinical data are moving toward the use of precision medicine in GI cancer. Here we review the application and status of precision medicine in GI cancer. Analyses of liquid biopsy specimens provide comprehensive real-time data of the tumor-associated changes in an individual GI cancer patient with malignancy. With the introduction of gene panels including next-generation sequencing, it has become possible to identify a variety of mutations and genetic biomarkers in GI cancer. Although the genomic aberration of GI cancer is apparently less actionable compared to other solid tumors, novel informative analyses derived from comprehensive gene profiling may lead to the discovery of precise molecular targeted drugs. These progressions will make it feasible to incorporate clinical, genome-based, and phenotype-based diagnostic and therapeutic approaches and apply them to individual GI cancer patients for precision medicine.     

Historical perspective: Two decades of progress in treating metastatic colorectal cancer

Colorectal cancer is the third most commonly diagnosed cancer in the United States. While screening methods strive to improve rates of early stage detection, 25% of patients have metastatic disease at the time of diagnosis, with the most common sites being the liver, lung, and peritoneum. While once perceived as hopeless, the last two decades have seen substantial strides in the medical, surgical, and regional therapies to treat metastatic disease offering significant improvements in survival.     

Cyclooxygenases, prostanoids, and tumor progression

In response to various growth factors, hormones or cytokines, arachidonic acid can be mobilized from phospholipids pools and converted to bioactive eicosanoids through cyclooxygenase (COX), lipoxygenase (LOX) or P-450 epoxygenase pathway. The COX pathway generates five major prostanoids (prostaglandin D₂, prostaglandin E₂, prostaglandin , prostaglandin I₂ and thromboxane A₂) that play important roles in diverse biological processes. Studies suggest that different prostanoids and their own synthase can play distinct roles in tumor progression and cancer metastasis. COX-2 and PGE₂ synthase have been most well documented in the regulation of various aspects of tumor progression and metastasis. PGE₂, for example, can stimulate angiogenesis or other signaling pathways by binding to its receptors termed EPs. Therefore, targeting downstream prostanoids may provide a new avenue to impede tumor progression. In this review, aberrant expression and functions of several prostanoid synthetic enzymes in cancer will be discussed. The possible regulation of tumor progression by prostaglandins and their receptors will also be discussed.     

Cancer stem cells in hepatocellular carcinoma: Recent progress and perspective

Although the “cancer stem cell (CSC)” hypothesis was first proposed roughly 50 years ago, recent progress in stem cell biology and technologies has successfully achieved the identification of CSCs in a variety of cancers. CSCs are defined as a minor population which possesses a prominent ability to generate new tumors that faithfully reproduce the phenotype of original tumors in xenotransplant assays. Additionally, CSCs are able to self-renew and generate differentiated progenies to organize a hierarchical cell system in a similar fashion to normal stem cells. Although not all types of cancer follow the CSC theory, it provides an attractive cellular mechanism to account for the therapeutic resistance and recurrence of the disease. A minor population with CSC properties has been detected in a number of established hepatocellular carcinoma (HCC) cell lines and extensive analyses characterizing the CSC system in primary HCC samples are now ongoing. Considering that HCC has high rates of recurrence and mortality, novel therapeutic approaches are urgently required. Although the clinical relevance of CSCs remains elusive, deep understanding of the cellular organization of HCC may allow us to develop therapies targeting specific cell types such as CSCs.     

Fatigue in cancer: a phenomenological perspective

Fatigue is a frequently encountered symptom in cancer populations. This study aimed to describe the experience of fatigue from the perspective of cancer patients who had recently completed a course of chemotherapy. A phenomenological method was used. The themes which emerged from the data indicated both a shared and individual experience of fatigue. These incorporated: the nature of fatigue; the causes, consequences, strategies for coping with fatigue; and the trajectory of the fatigue experience. Issues arising from the nature of phenomenological inquiry and the research were also elicited from this study. An understanding of the fatigue experience for this population and the use of phenomenology have implications for the nursing profession's knowledge base and for clinical practice.     

Melatonin in cancer management: progress and promise

Physiologic and pharmacologic concentrations of the pineal hormone melatonin have shown chemopreventive, oncostatic, and tumor inhibitory effects in a variety of in vitro and in vivo experimental models of neoplasia. Multiple mechanisms have been suggested for the biological effects of melatonin. Not only does melatonin seem to control development alone but also has the potential to increase the efficacy and decrease the side effects of chemotherapy when used in adjuvant settings. This review critically evaluates progress in the ability of melatonin to prevent or reverse cancer development and progression. We also discuss future prospects of the possible development of melatonin as a chemopreventive agent.     

Targeting MET in cancer: rationale and progress

Uncontrolled cell survival, growth, angiogenesis and metastasis are essential hallmarks of cancer. Genetic and biochemical data have demonstrated that the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the tyrosine kinase MET, have a causal role in all of these processes, thus providing a strong rationale for targeting these molecules in cancer. Parallel progress in understanding the structure and function of HGF/SF, MET and associated signalling components has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors. In this Review, we discuss these advances, as well as results from recent clinical studies that demonstrate that inhibiting MET signalling in several types of solid human tumours has major therapeutic value.     

Progress in ovarian cancer: an overview and perspective

Ovarian cancer remains the number one gynecologic killer in the Western world. However, there has been significant progress in understanding the genetics of ovarian cancer and in development of more effective therapies. The current optimum approach to therapy consists of cytoreductive surgery followed by combination chemotherapy. Clinical trials have established that carboplatin plus a taxane (usually paclitaxel) can be considered to be the treatment of choice for most patients with advanced disease. Most patients will achieve a clinical complete remission with such a combination. However, the median time to progression is less than 2 years, and for patients with optimal stage III disease, median survival will be approximately 5 years. Clinical trials are currently evaluating new combination chemotherapy regimens and the role of maintenance therapy in improving time to progression and overall survival. There has been a great deal of progress in understanding the genetics of epithelial ovarian cancer. The relationship between mutations in BRCA1 and BRCA2 genes and inherited predisposition to ovarian cancer has been of major clinical importance. While 90% of ovarian cancer cases are still considered to be sporadic, identification of the molecular events associated with hereditary ovarian cancer will lead to an increased understanding of the pathogenesis of sporadic disease as well since the two diseases share many clinical features. Development of high throughput screening methodology, such as CDNA microarray analysis, will lead to identification of additional genes which are important in the development of ovarian cancer, and will help define new targets for therapy and prevention as well as potential new biomarkers for early detection. The next generation of clinical trials will be focused on evaluating chemotherapy together with new molecular therapies, such as signal transduction inhibitors, anti-angiogenesis agents, and inhibitors of matrix metalloproteinases.     

Cyclins and cdks in development and cancer: a perspective

A fundamental aspect of cancer is dysregulated cell cycle control. Unlike normal cells that only proliferate when compelled to do so by developmental or other mitogenic signals in response to tissue growth needs, the proliferation of cancer cells proceeds essentially unchecked. This does not mean that cancer cell cycles are necessarily different from those found in normal cycling cells, but rather implies that cancer cells proliferate because they are no longer subject to proliferation-inhibitory influences arising from the stroma or from gene expression pattern changes consequent to 'terminal' differentiation, nor do they necessarily require extrinsic growth factors to recruit them into or maintain their proliferative state. Finally, cancer cells have also often avoided normal controls linked to cell cycle progression that halt proliferation in the presence of damaged DNA or other physiological insults. The result of these alterations is the inappropriate proliferation commonly associated with cancerous tumor formation. This review will summarize the current understanding of dysregulation of the G0/G1-to-S-phase transition in cancer cells, with particular emphasis on recent in vivo studies that suggest a need to rethink existing models of cell cycle control in development and tumorigenesis.     

Gallbladder cancer: a global perspective

Gallbladder cancer, the commonest malignancy of the biliary tract worldwide, is common in northern India. It can be clinically obvious, an unexpected finding at laparotomy, detected incidentally on histological examination or may be missed only to present with recurrence during follow up. US, CECT, uppeer gastro-intestinal endoscopy, and laparoscopy are useful for diagnosis and staging. We have adopted a 'middle path'--between pessimistic nihilism of the West and aggressive radicalism of Japan--of management, i.e., extended cholecystectomy for early disease confined to the gallbladder and hepato-dudodenal ligament, and non-surgical palliation for advanced disease. The aetiological role of gallstones in the causation of gallbladder cancer needs to be investigated to decide the place of prophylactic cholecystectomy, if any.     

Comprehensive cancer control: progress and accomplishments

The potential for Comprehensive Cancer Control (CCC) across the nation has been realized in the last decade with 69 Coalitions developing and implementing CCC plans. Many partners at all levels—national, state, jurisdictional, tribal and communities—have contributed to this success. This article details the contribution of these partners across these various levels, with a selection of the many activities contributing to this success. Consequently the cancer burden, although still of major importance, continues to be addressed in significant ways. Although there are future challenges, CCC coalitions continue to play an important role in addressing the cancer burden.     

Disparity in cancer care: a Canadian perspective

Canada is facing cancer crisis. Cancer has become the leading cause of death in Canada. Despite recent advances in cancer management and research, growing disparities in cancer care have been noticed, especially in socio-economically disadvantaged groups and under-served communities. With the rising incidence of cancer and the increasing numbers of minorities and of social disparities in general, and without appropriate interventions, cancer care disparities will become only more pronounced. This paper highlights the concepts and definitions of equity in health and health care and examines several health determinants that increase the risk of cancer. It also reviews cancer care inequity in the high-risk groups. A conceptual framework is proposed and recommendations are made for the eradication of disparities within the health care system and beyond.     

Ovarian cancer: progress and continuing controversies in management

Ovarian cancer is the most lethal of the gynaecological cancers, affecting approximately 1 in 75 women in the developed world. In most cases (>75%), the disease is disseminated beyond the ovary at diagnosis. For patients with stage III-IV disease, many clinicians agree that standard treatment should comprise six cycles of paclitaxel-carboplatin. Randomised trials over the past 10 years have indicated the superiority of paclitaxel-based treatment and that carboplatin is equivalent to cisplatin, but better tolerated. A recent trial has suggested that docetaxel may be a better option than paclitaxel, with reduced neurotoxicity and comparable efficacy. Overall treatment results remain unsatisfactory, since the median survival for these patients is 2-3 years. Future progress may be made by addressing the following issues: Would sequential regimes be more effective? Intriguing results from two large randomised trials (ICON-3 and GOG-132) indicate that single agent platinum might well be incorporated into such regimes. Additionally, a range of other agents could be tested as part of first-line regimes, having demonstrated activity in relapsed patients; these include topotecan, gemcitabine and liposomal doxorubicin. Newer agents, such as cell signalling inhibitors have shown potential as single agents, but may be particularly effective in combination with current drugs. Real progress can be expected when a better understanding is achieved of the mechanisms underlying clinical drug resistance in ovarian cancer, and a close laboratory-clinical interaction is crucial.     

Anaplastic lymphoma kinase: Role in cancer and therapy perspective

Anaplastic lymphoma kinase (ALK) is correlated with oncogenesis in different types of cancers, such as anaplastic large cell lymphoma, lung cancer, neuroblastoma, and even breast cancer, by abnormal fusion of ALK or non-fusion ALK activation. ALK is a receptor tyrosine kinase, with a single transmembrane domain, that plays an important role in development. Upon ligand binding to the extracellular domain, the receptor undergoes dimerization and subsequent autophosphorylation of the intracellular kinase domain. In recent years, ALK inhibitors have been developed for cancer treatment. These inhibitors target ALK activity and show effectiveness in ALK-positive non-small cell lung cancer. However, acquired treatment resistance makes the future of this therapy unclear; new strategies are underway to overcome the limitations of current ALK inhibitors.