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Reports on neoplastic processes in snakes are sparse regardless of their location, origin or behavior. Here, we describe the occurrence of multifocal cutaneous neoplastic processes consistent with hemangioma and hemangioendothelioma, with a differential diagnosis of angiomatosis, in a colony of native Brazilian rainbow boas (Epicrates cenchria) which also included animals affected by boid inclusion body disease (BIBD). Thirteen snakes were affected; seven of these had been introduced from other Brazilian sites years earlier, the others had been bred in house but were not offspring of knowingly affected animals. The breeding regime allowed contact between all female and male animals over the years. The cutaneous lesions were first observed over eight years ago, with additional cases detected during the three following years, but no new cases in the last five years. Two affected animals were subjected to a post mortem examination and were found to suffer from peliosis hepatis as one of the additional pathological changes. BIBD was confirmed in five of the eight examined animals, by histology, immunohistology for reptarenavirus nucleoprotein, and multiplex RT-PCR targeting the reptarenavirus S segment. Reptarenavirus infection was also detected in cells in the cutaneous neoplastic processes. PCRs for Bartonella henselae and B. quintana as well as bacterial DNA in general, performed on a pool of six skin lesions, yielded negative results, ruling out ongoing bacterial infection, like bacillary angiomatosis in humans, of the lesions. The results hint towards an association of reptarenavirus infection and BIBD with neoplastic processes which is worth further investigations.

Mathematical modeling, analysis and simulation are set to play crucial roles in explaining tumor behavior, and the uncontrolled growth of cancer cells over multiple time and spatial scales. This book, the first to integrate state-of-the-art numerical techniques with experimental data, provides an in-depth assessment of tumor cell modeling at multiple scales. The first part of the text presents a detailed biological background with an examination of single-phase and multi-phase continuum tumor modeling, discrete cell modeling, and hybrid continuum-discrete modeling. In the final two chapters, the authors guide the reader through problem-based illustrations and case studies of brain and breast cancer, to demonstrate the future potential of modeling in cancer research. This book has wide interdisciplinary appeal and is a valuable resource for mathematical biologists, biomedical engineers and clinical cancer research communities wishing to understand this emerging field.

Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC–immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.This Perspective discusses the signalling programmes and biological factors that simultaneously induce cancer stem cells and reprogramme the immune response to facilitate tumour immune evasion. It also highlights therapeutic opportunities for simultaneous targeting of the cancer stem cell niche and immunosurveillance.

Key Points To form metastases, cancer cells twice cross the endothelial cells that line blood vessels (once during intravasation and once during extravasation). Cancer cell extravasation usually occurs in small capillaries, where the cells can be physically trapped by size restriction and can then form stable attachments to endothelial cells. Many pairs of ligand–receptor molecules contribute to the process of extravasation, including selectins, integrins, cadherins, CD44 and immunoglobulin superfamily receptors. Cancer cells that are attached to endothelial cells interact with many other circulating cells in the bloodstream, including platelets, monocytes, neutrophils and natural killer cells, and these cells modulate the efficiency of cancer cell extravasation. Cytokines and chemokines that increase endothelial barrier permeability (and therefore increase the efficiency of cancer cell extravasation) are often secreted by cancer cells or by associated circulating cells. The processes of intravasation and extravasation are thought to be crucial for cancer cell dissemination and metastasis. This Review describes how cancer cells cross the endothelial barrier, with a focus on the extravasation step. During metastasis, cancer cells disseminate to other parts of the body by entering the bloodstream in a process that is called intravasation. They then extravasate at metastatic sites by attaching to endothelial cells that line blood vessels and crossing the vessel walls of tissues or organs. This Review describes how cancer cells cross the endothelial barrier during extravasation and how different receptors, signalling pathways and circulating cells such as leukocytes and platelets contribute to this process. Identification of the mechanisms that underlie cancer cell extravasation could lead to the development of new therapies to reduce metastasis.

Neutrophils play a key role in defence against infection and in the activation and regulation of innate and adaptive immunity. In cancer, tumour-associated neutrophils (TANs) have emerged as an important component of the tumour microenvironment. Here, they can exert dual functions. TANs can be part of tumour-promoting inflammation by driving angiogenesis, extracellular matrix remodelling, metastasis and immunosuppression. Conversely, neutrophils can also mediate antitumour responses by direct killing of tumour cells and by participating in cellular networks that mediate antitumour resistance. Neutrophil diversity and plasticity underlie the dual potential of TANs in the tumour microenvironment. Myeloid checkpoints as well as the tumour and tissue contexture shape neutrophil function in response to conventional therapies and immunotherapy. We surmise that neutrophils can provide tools to tailor current immunotherapy strategies and pave the way to myeloid cell-centred therapeutic strategies, which would be complementary to current approaches.This Review discusses the emerging dual role played by neutrophils in the tumour microenvironment as part of tumour-promoting inflammation, while also mediating antitumour immune responses, and suggests that neutrophil function could be manipulated in myeloid cell-based therapeutic approaches to improve patient outcomes.

Immunotherapy with checkpoint blockade induces rapid and durable immune control of cancer in some patients and has driven a monumental shift in cancer treatment. Neoantigen-specific CD8+ T cells are at the forefront of current immunotherapy strategies, and the majority of drug discovery and clinical trials revolve around further harnessing these immune effectors. Yet the immune system contains a diverse range of antitumour effector cells, and these must function in a coordinated and synergistic manner to overcome the immune-evasion mechanisms used by tumours and achieve complete control with tumour eradication. A key antitumour effector is the natural killer (NK) cells, cytotoxic innate lymphocytes present at high frequency in the circulatory system and identified by their exquisite ability to spontaneously detect and lyse transformed or stressed cells. Emerging data show a role for intratumoural NK cells in driving immunotherapy response and, accordingly, there have been renewed efforts to further elucidate and target the pathways controlling NK cell antitumour function. In this Review, we discuss recent clinical evidence that NK cells are a key immune constituent in the protective antitumour immune response and highlight the major stages of the cancer–NK cell immunity cycle. We also perform a new analysis of publicly available transcriptomic data to provide an overview of the prognostic value of NK cell gene expression in 25 tumour types. Furthermore, we discuss how the role of NK cells evolves with tumour progression, presenting new opportunities to target NK cell function to enhance cancer immunotherapy response rates across a more diverse range of cancers.This Review discusses the key role that natural killer (NK) cells play in driving an antitumour immune response throughout the progression of cancer from its initial development to its metastatic spread and eventual treatment, defined herein as the cancer–NK cell immunity cycle.

Metastatic dissemination occurs very early in the malignant progression of a cancer but the clinical manifestation of metastases often takes years. In recent decades, 5-year survival of patients with many solid cancers has increased due to earlier detection, local disease control and adjuvant therapies. As a consequence, we are confronted with an increase in late relapses as more antiproliferative cancer therapies prolong disease courses, raising questions about how cancer cells survive, evolve or stop growing and finally expand during periods of clinical latency. I argue here that the understanding of early metastasis formation, particularly of the currently invisible phase of metastatic colonization, will be essential for the next stage in adjuvant therapy development that reliably prevents metachronous metastasis.Metastatic dissemination can occur early during cancer progression, yet clinically overt metastases are often not detected for many years after surgical removal of the primary tumour. In this Perspective, Klein argues that understanding the ‘invisible’ phase of metastatic colonization is necessary to explain this phenomenon and develop better therapies to prevent metastasis.

Key Points Inhibitor of DNA binding (ID) proteins are a family of highly conserved transcriptional regulators that are pivotal both during developmental processes and in adult tissue homeostasis. ID proteins function by inhibiting basic helix–loop–helix, ETS and paired box (PAX) transcription factors and non-transcription factors of the RB family. The major biological effect of ID protein activity is the inhibition of differentiation and maintenance of self-renewal and multipotency in stem cells, and this is coordinated with continuous cell cycling. ID proteins are essential components of oncogenic pathways and are activated transcriptionally and post-transcriptionally by oncogenic factors. ID proteins are repressed by tumour suppressors although they have also been shown to function as tumour suppressors in specific tumour types. ID proteins are overexpressed in many human cancers and deregulation of ID proteins has a direct role in cancer initiation, maintenance, progression and drug resistance. The expression of ID proteins has a prognostic value in many human cancers and interfering with ID activity in tumours that have ID protein activation might provide new avenues for cancer treatment. Inhibitor of DNA binding (ID) proteins are transcriptional regulators that control the timing of cell fate determination and differentiation in stem and progenitor cells. The ability of ID proteins to function as central 'hubs' for the coordination of multiple cancer hallmarks is establishing them as therapeutic targets and biomarkers in specific types of human tumours. Inhibitor of DNA binding (ID) proteins are transcriptional regulators that control the timing of cell fate determination and differentiation in stem and progenitor cells during normal development and adult life. ID genes are frequently deregulated in many types of human neoplasms, and they endow cancer cells with biological features that are hijacked from normal stem cells. The ability of ID proteins to function as central 'hubs' for the coordination of multiple cancer hallmarks has established these transcriptional regulators as therapeutic targets and biomarkers in specific types of human tumours.

Key Points During the past decade, the metabolic alterations that intimately accompany oncogenesis and tumour progression have been intensively investigated, generating great expectations on the development of novel antineoplastic agents that would selectively target the metabolism of malignant cells. With the notable exception of oncometabolites, the metabolism of cancer cells resembles very much that of any rapidly proliferating cell, exhibiting a prominent shift towards anabolic reactions and an increased dependency on intermediates and pathways that — directly or indirectly — sustain such an accelerated biosynthetic activity. At least in some settings, systemic metabolism exerts a prominent influence on carcinogenesis and tumour progression. This is best exemplified by the increased risk of developing cancer that accompanies metabolic syndromes such as diabetes and obesity as well as by the antineoplastic effects of several drugs that are currently used for the treatment of these conditions. The extensive metabolic rewiring of malignant cells is not yet another hallmark of cancer but instead a process that intervenes along with — and hence cannot be discriminated from — oncogenesis. In line with this notion, multiple oncogenes (for example, MYC ) and oncosuppressor genes (for example, the tumour suppressor p53 gene TP53 ) have been shown to regulate bioenergetic and anabolic metabolic circuitries. The accumulation of metabolic intermediates such as fumarate, succinate and 2-hydroxyglutarate suffices to drive oncogenesis, at least in some settings. The existence of such oncometabolites reinforces the notion that the metabolic rearrangements of malignant cells are not a mere epiphenomenon of oncogenesis but one of its crucial components. A huge amount of preclinical data and accumulating clinical experience indicate that several metabolic circuitries can be efficiently targeted to achieve antineoplastic effects in vivo . Thus, in spite of an essential similarity between the metabolism of cancer cells and that of any highly proliferating cell, a therapeutic window exists for this promising approach to treat cancer. Cellular metabolism is substantially altered during oncogenesis and tumour progression, and targeting these metabolic changes is being actively pursued in the development of selective antineoplastic agents. Here, Kroemer and colleagues discuss the intimate relationship between metabolism and malignancy, focusing on therapeutic strategies and emerging agents targeting the metabolic rearrangements of cancer cells. Malignant cells exhibit metabolic changes, when compared to their normal counterparts, owing to both genetic and epigenetic alterations. Although such a metabolic rewiring has recently been indicated as yet another general hallmark of cancer, accumulating evidence suggests that the metabolic alterations of each neoplasm represent a molecular signature that intimately accompanies and allows for different facets of malignant transformation. During the past decade, targeting cancer metabolism has emerged as a promising strategy for the development of selective antineoplastic agents. Here, we discuss the intimate relationship between metabolism and malignancy, focusing on strategies through which this central aspect of tumour biology might be turned into cancer's Achilles heel.

Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours.The hostile microenvironment of the tumour can disrupt endoplasmic reticulum (ER) homeostasis in cancer cells and infiltrating immune cells to result in a state of ER stress. This Review discusses how ER stress can influence not only the pro-tumoural features of cancer cells but also reprogramme the function of innate and adaptive immune cells, creating vulnerabilities that could be targeted by emerging therapeutic strategies.