Identifying drivers of metastasis; towards a systematic approach
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Abstract:
Metastasis is incontrovertibly linked to poor cancer patient survival. Cancer treatments that inhibit metastasis are predicted to improve cancer patient outcomes by preventing cancer dissemination. However, to control metastasis in patients necessitates an understanding of the biological drivers of metastasis. Drivers of metastasis can be thought of as factors that promote tumour dissemination, required at least for a part of the metastatic process. Yet, presently specific molecular drivers of metastasis largely remain unidentified, and very little evidence for ubiquitous metastasis-specific driver gene mutations has been identified to date (1,2).Cite
Cancer metastasis, a complex and sequential network of cellular events involved in the migration and establishment of malignant cells from original site to distant foci, is an important and significant contributor to morbidity and mortality of cancer patients. Despite the clinical importance of cancer metastasis, its molecular and biochemical mechanism remains unclear. The identification of tumor suppressor gene confirmed that metastasis might involve the functional loss of genes that maintain the cellular differentiation optimally. Metastasis suppressor is defined by the ability to reduce the metastatic property of cancer cells without affecting its tumorigenesis. Since NM23 was first identified in 1988 as a metastasis suppressor, several metastasis suppressor genes have been identified and characterized. In this article, we review the complex and multi-step process of cancer metastasis and describe the recent progress of metastasis suppressors in the studies of identified. Consequently, we hope to introduce the new therapeutic target for the metastasis suppressors in cancer patients.
Metastasis Suppressor Gene
Metastasis suppressor
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Metastasis, is a development of secondary tumor growths at a distance from the primary site, and closely related to poor prognosis and mortality. However, there is still no effective treatment for metastatic cancer. Therefore, there is an urgent need to find an effective therapy for cancer metastasis. Plenty of evidence indicates that miR-9 can function as a promoter or suppressor in cancer metastasis and coordinate multistep of metastatic process. In this review, we summarize the different roles of miR-9 with the corresponding molecular mechanisms in metastasis of twelve common cancers and the multiple mechanisms underlying miR-9-mediated regulation of metastasis, benefiting the further research of miR-9 and metastasis, and hoping to bridge it with clinical applications.
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การแพรกระจายของมะเรง และเปาหมายสำหรบการรกษา พทธพร แกวมศร , ลดดาวลย เสงกนไพร* ภาควชาเภสชวทยา คณะแพทยศาสตร มหาวทยาลยขอนแกน การแพรกระจายของมะเรงเปนกระบวนการทเซลลมะเรงกระจายไปยงสวนตางๆ ของรางกาย ซงพบวามะเรงในระยะแพรกระจายเปนสาเหตหลกททำใหผปวยเสยชวต การแพรกระจายของเซลลมะเรงประกอบดวยการทำงานหลายขนตอนและมโมเลกลทเกยวของหลายชนด การศกษากลไกในระดบโมเลกล เพอดบทบาทและการทำงานของโมเลกลเหลาน เปนพนฐานสำคญทนำไปสการศกษาคนควาตอยอดเพอหาแนวทางการรกษามะเรงแพรกระจาย ในปจจบนมสารหลายชนดทอยในขนตอนการศกษาทางคลนก โดยมงเปาการออกฤทธไปทโมเลกลทจำเพาะเจาะจงในกระบวนการแพรกระจายของเซลลมะเรง ซงมความคาดหวงวาจะทำใหลดอตราการสญเสยชวตจากโรคมะเรงได Metastasis is a process that cancer cells spread from a primary site to different parts of the body. It is the major cause of cancer death. The metastasis involved multiple sequential steps in which numerous biochemical molecules have been implicated in the process. Insight understanding the role of such molecular components is important for metastasis prevention and inhibition. To produce clinically effective therapeutic outcomes, several compounds targeting metastasis processes have been developed and are currently under study in various phases of clinical testing for treatment of metastatic cancers, in expectation, further reduce cancer mortality rate.
Cancer Treatment
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Metastasis is an enormously complex process that remains to be a major problem in the management of cancer. The fact that cancer patients might develop metastasis after years or even decades from diagnosis of the primary tumor makes the metastatic process even more complex. Over the years many hypotheses were developed to try to explain the inefficiency of the metastatic process, but none of these theories completely explains the current biological and clinical observations. In this review we summarize some of the proposed models that were developed in attempt to understand the mechanisms of tumor dissemination and colonization as well as metastatic progression.
Surgical oncology
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Metastasis is the most lethal attribute of a cancer. There is a critical need for markers that will accurately distinguish those histologic lesions and disseminated cells that have a high probability of causing clinically important metastatic disease from those cells that will remain indolent. Despite the explosion in new information regarding the genetics of cancer, only six human genes have thus far been shown to functionally suppress metastasis. The present review and perspective describes the evolving view of the mechanisms that regulate metastasis, and the importance of metastasis-suppressor genes in this process. Specifically, the clinical problem of metastatic prostate cancer, the identification of metastatic colonization as a therapeutic target, and the identification and functional characterization of prostate cancer metastasis-suppressor genes are discussed.
Metastasis Suppressor Gene
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Metastasis, the development of secondary malignant growths at a distance from the primary site of a cancer, is associated with almost 90% of all cancer deaths, and half of all cancer patients present with some form of metastasis at the time of diagnosis. Consequently, there is a clear clinical need for a better understanding of metastasis. The role of miRNAs in the metastatic process is beginning to be explored. However, much is still to be understood. In this review, we present the accumulating evidence for the importance of miRNAs in metastasis as key regulators of this hallmark of cancer.
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Introduction: Metastatic cancers are extremely difficult to treat, and account for the vast majority of cancer-related deaths. The dissemination of tumor cells to distant sites is highly dynamic, asynchronous, and involves both tumor and host intrinsic factors. Effective therapeutic targets to block metastasis will need to disrupt key pathways that are required for multiple stages of metastasis.Areas covered: This review discusses the heterogeneity of cancers and metastasis, with an emphasis on motility as a key driver trait of metastasis. Recent metastatic cancer studies that identified either host or cancer cell intrinsic factors important for metastasis, using single gene-deficient animal models or 3D intravital imaging of avian embryo models, are also discussed. Potential metastatic blocking targets are listed as they relate to metastatic cancer therapy.Expert opinion: The development of metastatic disease is a complex interplay of genetic and epigenetic factors from the host and cancer cells acting in a patient-specific manner. Inhibiting key driver traits of metastasis should yield survival benefit at any stage of the disease, and we look forward to the next generation of personalized medicines for cancer therapy that target cancer cell motility for increased therapeutic efficacy.
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With improvements in surgical procedures and cure rates, the probable course of cancer for the majority of patients is now largely determined by metastasis rather than growth of the primary tumor itself. Thus, metastasis has received increasing attention over the past decade. These studies have led to the identification of several of the molecular events crucial for metastatic dissemination, information which is now being used to design therapeutic strategies to inhibit metastasis formation. Even though the molecular events involved in the dissemination of malignant disease are only partially known, several promising agents are now being tested for their capacity to limit the spread of cancer. A few clinical trials have shown benefit in prolonging survival and disease-free state, particularly when such therapy is employed on an adjuvant basis.
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Cancer is one of the main reasons of mortality worldwide, and more than 90 percent of cancer deaths are due to metastasis. Although primary tumors are curable using chemical adjuvant therapy or surgery, metastatic tumors are mostly incurable. This resistance shows the high rate of mortality among patients with metastatic disease. Being a sequential event, metastasis is a subtle and intricate process in which tumor cells undergo a plenty of changes and acquire the capacity of migration, invasion, survival and self-renewal which all are necessary for metastasis to happen. The key point in recognition and cure in invasive cancers is to identify critical genes, proteins and pathways involved, and show their relation with each other and the disease. Forming metastasis needs favorable genetic and microenvironmental elements of tumor cells and distant tissue, respectively. Unfavorable conditions in each steps of this process lead to arresting metastasis and subsequent dormancy, which is the most important phenomenon in relapse. In this review, benefiting from tens of reliable and recently identified data and personal experiences, it has been tried to draw new patterns associated with metastasis for further investigation. Determining genes, proteins and microenvironmental factors that affect metastasis, in a sequential manner, can help better understanding of this lethal process and subsequently a prosperous treatment.
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Metastasis remains the main cause of death in cancer patients, and current treatment options are insufficient. There is a great need to define new strategies. The process of metastasis is regulated by specific sets of metastasis genes. Whereas some metastasis genes may be common for all cancers, some may be specific for distinct cancer types. Characterization of such genes holds great promise for the future because they may serve as targets for disease monitoring and therapy. In the past, two parallel but individually incomplete genomic approaches were established to define such genes, the in-vivo selection of derivative cell lines with high metastatic potential and gene expression profiling of human tumor tissue. However, each approach is associated with pitfalls, a reason that may account for the relatively poor overlap of findings among different groups. Therefore, rigorous validation of the biological relevance of such metastasis genes for distinct cancer types is of the utmost importance.
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