Metastasis as an evolutionary process

The progression of cancer is an evolutionary process. During this process, evolving populations of cancer cells encounter restrictive ecological niches within the body, such as the primary tumor, the circulatory system, and diverse metastatic sites. Heterogeneous populations of cancer cells undergo selection for adaptive phenotypes, which shapes molecular genetic variation amid concomitant genetic drift. Cell lineages undergo convergent evolution toward phenotypes known as the hallmarks of cancer that promote cancer initiation, growth, and metastasis...

Background: Tumors exhibit extensive intra-tumor heterogeneity, the presence of groups of cellular populations with distinct sets of somatic mutations. This heterogeneity is the result of an evolutionary process, described by a phylogenetic tree. In addition to enabling clinicians to devise patient-specific treatment plans, phylogenetic trees of tumors enable researchers to decipher the mechanisms of tumorigenesis and metastasis. However, the problem of reconstructing a phylogenetic tree T given bulk sequencing data from a tumor is more complicated than the classic phylogeny inference problem...

The term "autophagy", which means "self (auto) - eating (phagy)", describes a catabolic process that is evolutionarially conserved among all eukaryotes. Although autophagy is mainly accepted as a cell survival mechanism, it also modulates the process known as "type II cell death". AKT/mTOR pathway is an upstream activator of autophagy and it is tightly regulated by the ATG (autophagy-related genes) signaling cascade. In addition, wide ranging cell signaling pathways and non-coding RNAs played essential roles in the control of autophagy...

Prostate cancer (PC) is a leading cause of death in men. Inflammation is one of the initiating processes whereby cells are trafficked into the tumor microenvironment by specific cytokines termed chemokines. This recruitment is complex and involves diverse leukocyte subsets with procancer and anticancer functions. Chemokines promote/abrogate proliferation of cancerous cells, block/aid apoptosis, and are instrumental/detrimental in cancer cell migration required for metastasis. Chemokines guide the release/transport of immune cells that serve as chaperones at sites of inflammation, and after subsequent activation, they lead to an immune response...

Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts. Here we characterize the evolutionary dynamics of this lethal process by analyzing exome-sequencing data from 118 biopsies from 23 patients with colorectal cancer with metastases to the liver or brain. The data show that the genomic divergence between the primary tumor and metastasis is low and that canonical driver genes were acquired early. Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%, 17 out of 21 evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0...

Many cancers possess an incorrect number of chromosomes, a state described as aneuploidy. Aneuploidy is often caused by Chromosomal Instability (CIN), a process of continuous chromosome mis-segregation. CIN is believed to endow tumours with enhanced evolutionary capabilities due to increased intratumour heterogeneity, and facilitating adaptive resistance to therapies. Recently, however, additional consequences and associations with CIN have been revealed, prompting the need to understand this universal hallmark of cancer in a multifaceted context...

Multistage tumorigenesis is a dynamic process characterized by the accumulation of mutations. Thus, a tumor mass is composed of genetically divergent cell subclones. With the advancement of next-generation sequencing (NGS), mathematical models have been recently developed to decompose tumor subclonal architecture from a collective genome sequencing data. Most of the methods focused on single-nucleotide variants (SNVs). However, somatic copy number aberrations (CNAs) also play critical roles in carcinogenesis...

Virulence is defined as the ability of a pathogen to cause morbidity and/or mortality in infected hosts. The relationship between virulence and transmissibility is complex; natural selection may promote decreased virulence to enhance host mobility and increase the probability for transmission, or transmissibility may be enhanced by increased virulence, leading to higher pathogen load and, in some cases, superior evasion from host defenses. An evolutionary trade-off exists between the ability of pathogens to maintain opportunities for long-term transmission via suppressed virulence and increased short-term transmission via enhanced virulence...

Pioneering studies described cancer as an evolutionary process and detailed its intratumor heterogeneity in patients' specimens. The development of unbiased single-cell sequencing technologies confirmed these early observations and neoplasms are now widely recognized as populations of genetically, chromosomally and epigenetically distinct cells in which clones carrying beneficial traits expand in presence of selection factors like chemotherapy treatment. In support of this view, intratumor heterogeneity, by providing a large pool of phenotypically distinct clones, was shown to correlate with poor prognosis, therapy failure and metastasis...

The major transitions approach in evolutionary biology has shown that the intercellular cooperation that characterizes multicellular organisms would never have emerged without some kind of multilevel selection. Relying on this view, the Evolutionary Somatic view of cancer considers cancer as a breakdown of intercellular cooperation and as a loss of the balance between selection processes that take place at different levels of organization (particularly single cell and individual organism). This seems an elegant unifying framework for healthy organism, carcinogenesis, tumour proliferation, metastasis and other phenomena such as ageing...

Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy of active systemic treatments, and a metastatic behavior, demonstrated throughout the evolution of the disease. On average, 80% of patients with PC are diagnosed with metastatic disease, and the half of those who undergo surgery and adjuvant therapy develop liver metastasis within two years. Metastatic dissemination is an early event in PC and is mainly attributed to an evolutionary biological process called epithelial-to-mesenchymal transition (EMT)...

Metastatic tumors are the cause of more than 90% of cancer related deaths. Metastasis formation can be considered as a culmination of the Darwinian evolutionary process within the tumor, when competition of multiple clones results in the development of cell inherent traits that favor tumor dissemination. Cancer stem cells (CSC) which possess self-renewal properties and genomic instability are considered to be an engine of tumor evolution. Cancer cells which have the capacity to colonize distant organs have the features of CSC and, in addition, exert their tumor-initiating capacity under adverse microenvironmental conditions...

BACKGROUND: Single-cell micro-metastases of solid tumors often occur in the bone marrow. These disseminated tumor cells (DTCs) may resist therapy and lay dormant or progress to cause overt bone and visceral metastases. The molecular nature of DTCs remains elusive, as well as when and from where in the tumor they originate. Here, we apply single-cell sequencing to identify and trace the origin of DTCs in breast cancer. RESULTS: We sequence the genomes of 63 single cells isolated from six non-metastatic breast cancer patients...

Intrahepatic cholangiocarcinoma (iCCA) comprises one of the most rapidly evolving cancer types. An underlying chronic inflammatory liver disease that precedes liver cancer development for several decades and creates a pro-oncogenic microenvironment frequently impairs progress in therapeutic approaches. Depending on the cellular target of malignant transformation, a large spectrum of molecular and morphological patterns is observed. As such, it is crucial to advance our existing understanding of the molecular pathogenesis of iCCA, particularly its genomic heterogeneity, to improve current clinical strategies and patient outcome...

Therapeutic advances in oncology have not fully translated to the treatment of metastatic disease, which remains largely incurable. Metastatic subclones can emerge both early and late in the life of the primary tumor. A better understanding of the genetic evolution of metastatic disease has the potential to reveal differences in the therapeutic vulnerabilities of primary and metastatic tumors, shed light on the temporal patterns of and routes to metastatic colonization, and provide insight into the biology of the metastatic process...

Galectins constitute an evolutionary conserved family that binds to β-galactosides. There is growing evidence that galectins are implicated in essential biological processes such as cellular communication, inflammation, differentiation and apoptosis. Galectin-3 is one of the best-known galectins, which is found in vertebrates. Galectin-3 has been shown to be expressed in some cell lines and plays important roles in several physiological and pathological processes, including cell adhesion, cell activation and chemoattraction, cell cycle, apoptosis, cell growth, and differentiation...

A major goal of modern medicine is increasing patient specificity so that the right treatment is administered to the right patient at the right time with the right dose. While current cancer studies have largely focused on identification of genetic or epigenetic properties of tumor cells, emerging evidence has clearly demonstrated substantial genetic heterogeneity between tumors in the same patient and within subclones of a single tumor. Thus, molecular analysis from populations of cells (either a whole tumor or small biopsy of that tumor) is, at best, an incomplete representation of the underlying biology...

MicroRNAs (miRNAs) are one of a growing class of noncoding RNAs that are involved in the regulation of a wide range of metabolic processes including cellular differentiation, cell proliferation and apoptosis. The generation of miRNA is regulated in complex ways, for example by small interfering RNAs (small nucleolar and nuclear RNAs) and various other metabolites. This complexity of control is likely to explain how a relatively small part of the DNA that codes for proteins has enabled the evolution of such complex organisms as mammals...

Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones...

"Cancer Bioinformatics" is a new book published in 2014 by Springer. This 14-chapter book offers a quite unique and potentially controversial view about what drives a cancer to initiate, progress, metastasize and develop in an accelerated manner in metastatic sites. The book treats cancer as an evolutionary process of a diseased tissue (rather than cells) in an increasingly more challenging microenvironment; and discusses the various stresses encountered by a neoplastic tissue and their roles in (driving) cancer initiation, progression, metastasis and post-metastatic development...