Vessel co-option in cancer Kuczynski, Elizabeth A; Vermeulen, Peter B; Pezzella, Francesco ...
Nature reviews. Clinical oncology,
08/2019, Letnik:
16, Številka:
8
Journal Article
Recenzirano
All solid tumours require a vascular supply in order to progress. Although the ability to induce angiogenesis (new blood vessel growth) has long been regarded as essential to this purpose, thus far, ...anti-angiogenic therapies have shown only modest efficacy in patients. Importantly, overshadowed by the literature on tumour angiogenesis is a long-standing, but continually emerging, body of research indicating that tumours can grow instead by hijacking pre-existing blood vessels of the surrounding nonmalignant tissue. This process, termed vessel co-option, is a frequently overlooked mechanism of tumour vascularization that can influence disease progression, metastasis and response to treatment. In this Review, we describe the evidence that tumours located at numerous anatomical sites can exploit vessel co-option. We also discuss the proposed molecular mechanisms involved and the multifaceted implications of vessel co-option for patient outcomes.
MicroRNAs (miRNAs) are an emerging class of gene expression modulators with relevant roles in several biological processes, including cell differentiation, development, apoptosis, and regulation of ...the cell cycle. Deregulation of those tiny RNA molecules has been described frequently as a major determinant for the initiation and progression of diseases, including cancer. Not only miRNAs but also the enzymes responsible for miRNA processing could be deregulated in cancer. In this review, we address the role of miRNAs in the pathogenesis of breast cancer, since there are oncogenic, tumor-suppressive, and metastatic-influencing miRNAs. Additionally, the different detection platforms and normalization strategies for miRNAs will be discussed. The major part of this review, however, will focus on the capability of miRNAs to act as diagnostic, predictive, or prognostic biomarkers. We will give an overview of their potential to correlate with response to or benefit from a given treatment and we will consider their ability to give information on prognosis in breast cancer. We will focus on miRNAs validated by more than one study or verified in independent cohorts or where results rely on preclinical as well as clinical evidence. As such, we will discuss their potential use in the personalized management of breast cancer.
Plant communities with traits that would maximize community performance can be invaded by plants that invest extra in acquiring resources at the expense of others, lowering the overall community ...performance, a so-called tragedy of the commons (TOC). By contrast, maximum community performance is usually the objective in agriculture. We first give an overview of the occurrence of TOCs in plants, and explore the extent to which past crop breeding has led to trait values that go against an unwanted TOC. We then show how linking evolutionary game theory (EGT) with mechanistic knowledge of the physiological processes that drive trait expression and the ecological aspects of biotic interactions in agro-ecosystems might contribute to increasing crop yields and resource-use efficiency.
Current increases in crop production are falling below the 2% annual rise needed to maintain global food security, while restrictions on the use of synthetic fertilizers and pesticides are increasing. This calls for new more ecology-based directions in crop breeding and management.
Optimal plant communities with maximum growth or seed production are often not stable against invasion by individuals that invest more in resource harvesting. These effects have been framed as TOCs and conflict with the need in agriculture for increased yields and ecosystem service provisioning.
Recently there is increased interest in assessing how these TOCs arise and how this knowledge in turn may give directions for crop breeding and management. Linking evolutionary game theory (EGT) – the key mathematical tool to analyze natural selection in situations where organisms interact – to our increased understanding of the physiological regulation of trait expression and ecological interactions in agro-ecosystems provides a framework through which this can be achieved.
Solid tumours need a blood supply, and a large body of evidence has previously suggested that they can grow only if they induce the development of new blood vessels, a process known as tumour ...angiogenesis. On the basis of this hypothesis, it was proposed that anti-angiogenic drugs should be able to suppress the growth of all solid tumours. However, clinical experience with anti-angiogenic agents has shown that this is not always the case. Reports of tumours growing without the formation of new vessels can be found in the literature dating back to the 1800s, yet no formal recognition, description and demonstration of their special biological status was made until recently. In 1996, we formally recognized and described non-angiogenic tumours in lungs where the only blood vessels present were those originating from normal lung tissue. This is far from an isolated scenario, as non-angiogenic tumour growth has now been observed in tumours of many different organs in both humans and preclinical animal models. In this Opinion article, we summarize how these tumours were discovered and discuss what we know so far about their biology and the potential implications of this knowledge for cancer treatment.
Different genotypes often exhibit opposite plastic responses in the timing of the onset of flowering with increasing plant density. In experimental studies, selection for accelerated flowering is ...generally found. By contrast, game theoretical studies predict that there should be selection for delayed flowering when competition increases.
Combining different optimality criteria, the conditions under which accelerated or delayed flowering in response to density would be selected for are analysed with a logistic growth simulation model.
To maximize seed production at the whole-stand level (simple optimization), selection should lead to accelerated flowering at high plant density, unless very short growing seasons select for similar onset of flowering at all densities. By contrast, selection of relative individual fitness will lead to delayed flowering when season length is long and/or growth rates are high.
These different results give a potential explanation for the observed differences in direction of the plastic responses within and between species, including homeostasis, as a result of the effect of the variation in season length on the benefits of delayed flowering. This suggests that limited plasticity can evolve without the costs and limits that are currently thought to constrain the evolution of plasticity.
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We ...found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can ...occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.
Intravascular dissemination of tumor cells is the accepted mechanism of cancer metastasis. However, the phenomenon of angiotropism, pericyte mimicry (PM), and extravascular migratory metastasis ...(EVMM) has questioned the concept that tumor cells metastasize exclusively via circulation within vascular channels. This new paradigm of cancer spread and metastasis suggests that metastatic cells employ embryonic mechanisms for attachment to the abluminal surfaces of blood vessels (angiotropism) and spread via continuous migration, competing with and replacing pericytes, i.e., pericyte mimicry (PM). This is an entirely extravascular phenomenon (i.e., extravascular migratory metastasis or EVMM) without entry (intravasation) into vascular channels. PM and EVMM have mainly been studied in melanoma but also occur in other cancer types. PM and EVMM appear to be a reversion to an embryogenesis-derived program. There are many analogies between embryogenesis and cancer progression, including the important role of laminins, epithelial–mesenchymal transition, and the re-activation of embryonic signals by cancer cells. Furthermore, there is no circulation of blood during the first trimester of embryogenesis, despite the fact that there is extensive migration of cells to distant sites and formation of organs and tissues during this period. Embryonic migration therefore is a continuous extravascular migration as are PM and EVMM, supporting the concept that these embryonic migratory events appear to recur abnormally during the metastatic process. Finally, the perivascular location of tumor cells intrinsically links PM to vascular co-option. Taken together, these two new paradigms may greatly influence the development of new effective therapeutics for metastasis. In particular, targeting embryonic factors linked to migration that are detected during cancer metastasis may be particularly relevant to PM/EVMM.
The liver is host to many metastatic cancers, particularly colorectal cancer, for which the last 2 decades have seen major advances in diagnosis and treatment. The liver is a vital organ, and the ...extent of its involvement with metastatic disease is a major determinant of survival. Metastatic cells arriving in the liver via the bloodstream encounter the microenvironment of the hepatic sinusoid. The interactions of the tumor cells with hepatic sinusoidal and extrasinusoidal cells (endothelial, Kupffer, stellate, and inflammatory cells) determine their fate. The sinusoidal cells can have a dual role, sometimes fatal to the tumor cells but also facilitatory to their survival and growth. Adhesion molecules participate in these interactions and may affect their outcome. Bone marrow-derived cells and chemokines also play a part in the early battle for survival of the metastases. Once the tumor cells have arrested and survived the initial onslaught, tumors can grow within the liver in 3 distinct patterns, reflecting differing host responses, mechanisms of vascularization, and proteolytic activity. This review aims to present current knowledge of the interactions between the host liver cells and the invading metastases that has implications for the clinical course of the disease and the response to treatment.
PDF
