Metastasis is the primary cause of cancer morbidity and mortality. The process involves a complex interplay between intrinsic tumor cell properties as well as interactions between cancer cells and ...multiple microenvironments. The outcome is the development of a nearby or distant discontiguous secondary mass. To successfully disseminate, metastatic cells acquire properties in addition to those necessary to become neoplastic. Heterogeneity in mechanisms involved, routes of dissemination, redundancy of molecular pathways that can be utilized, and the ability to piggyback on the actions of surrounding stromal cells makes defining the hallmarks of metastasis extraordinarily challenging. Nonetheless, this review identifies four distinguishing features that are required: motility and invasion, ability to modulate the secondary site or local microenvironments, plasticity, and ability to colonize secondary tissues. By defining these first principles of metastasis, we provide the means for focusing efforts on the aspects of metastasis that will improve patient outcomes.
Heterogeneity is commonplace in all cancer types and at several levels--intrinsic (genetic), epigenetic, positional, and at the population level. The different subpopulations with a tumor mass ...communicate with each other and influence the behavior of other tumor cells both locally and at a distance. These properties have profound implications regarding the understanding of tumor behavior and how therapies are (or should be) administered. This brief commentary highlights the insightful review of Gloria Heppner and how it has influenced cancer research even three decades after it was published.
Although mitochondrial contributions to cancer have been recognised for approximately a century, given that mitochondrial DNA (mtDNA) is dwarfed by the size of the nuclear genome (nDNA), nuclear ...genetics has represented a focal point in cancer biology, often at the expense of mtDNA and mitochondria. However, genomic sequencing and advances in in vivo models underscore the importance of mtDNA and mitochondria in cancer and metastasis. In this review, we explore the roles of mitochondria in the four defined 'hallmarks of metastasis': motility and invasion, microenvironment modulation, plasticity and colonisation. Biochemical processes within the mitochondria of both cancer cells and the stromal cells with which they interact are critical for each metastatic hallmark. We unravel complex dynamics in mitochondrial contributions to cancer, which are context-dependent and capable of either promoting metastasis or being leveraged to prevent it at various points of the metastatic cascade. Ultimately, mitochondrial contributions to cancer and metastasis are rooted in the capacity of these organelles to tune metabolic and genetic responses to dynamic microenvironmental cues.
Summary Most cancer deaths are due to the development of metastases, hence the most important improvements in morbidity and mortality will result from prevention (or elimination) of such disseminated ...disease. Some would argue that treatments directed against metastasis are too late because cells have already escaped from the primary tumour. Such an assertion runs contrary to the significant but (for many common adult cancers) fairly modest improvements in survival following the use of adjuvant radiation and chemotherapy designed to eliminate disseminated cells after surgical removal of the primary tumour. Nonetheless, the debate raises important issues concerning the accurate early identification of clonogenic, metastatic cells, the discovery of novel, tractable targets for therapy, and the monitoring of minimal residual disease. We focus on recent findings regarding intrinsic and extrinsic molecular mechanisms controlling metastasis that determine how, when, and where cancers metastasise, and their implications for patient management in the 21st century.
Present therapeutic approaches do not effectively target metastatic cancers, often limited by their inability to eliminate already-seeded non-proliferative, growth-arrested, or therapy-resistant ...tumor cells. Devising effective approaches targeting dormant tumor cells has been a focus of cancer clinicians for decades. However, progress has been limited due to limited understanding of the tumor dormancy process. Studies on tumor dormancy have picked up pace and have resulted in the identification of several regulators. This review focuses on KISS1, a metastasis suppressor gene that suppresses metastasis by keeping tumor cells in a state of dormancy at ectopic sites. The review explores mechanistic insights of KISS1 and discusses its potential application as a therapeutic against metastatic cancers by eliminating quiescent cells or inducing long-term dormancy in tumor cells.
Despite advancements in knowledge from more than a century of metastasis research, the genetic programs and molecular mechanisms required for cancer metastasis are still incompletely understood. ...Genes that specifically regulate the process of metastasis are useful tools to elucidate molecular mechanisms and may become markers and/or targets for antimetastatic therapy. Recently, several noncoding regulatory RNA genes, microRNA (miRNA), were identified, which play roles in various steps of metastasis, some without obvious roles in tumorigenesis. Understanding how these metastasis-associated miRNA, which we term metastamir, are involved in metastasis will help identify possible biomarkers or targets for the most lethal attribute of cancer: metastasis.
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