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"Carcinogenesis"
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Adaptive oncogenesis : a new understanding of how cancer evolves inside us
\"Popular understanding holds that genetic changes create cancer. James DeGregori uses evolutionary principles to propose a new way of thinking about cancer's occurrence. Cancer is as much a disease of evolution as it is of mutation, one in which mutated cells outcompete healthy cells in the ecosystem of the body's tissues. His theory ties cancer's progression, or lack thereof, to evolved strategies to maximize reproductive success. Through natural selection, humans evolved genetic programs to maintain bodily health for as long as necessary to increase the odds of passing on our genes--but not much longer. These mechanisms engender a tissue environment that favors normal stem cells over precancerous ones. Healthy tissues thwart cancer cells' ability to outcompete their precancerous rivals. But as our tissues age or accumulate damage from exposures such as smoking, normal stem cells find themselves less optimized to their ecosystem. Cancer-causing mutations can now help cells adapt to these altered tissue environments, and thus outcompete normal cells. Just as changes in a species' habitat favor the evolution of new species, changes in tissue environments favor the growth of cancerous cells. DeGregori's perspective goes far in explaining who gets cancer, when it appears, and why. While we cannot avoid mutations, it may be possible to sustain our tissues' natural and effective system of defense, even in the face of aging or harmful exposures. For those interested in learning how cancers arise within the human body, the insights in Cancer: Evolution Within Us offer a compelling perspective\"-- Provided by publisher.
Book
Gut microbiota carcinogen metabolism causes distal tissue tumours
Exposure to environmental pollutants and human microbiome composition are important predisposition factors for tumour development
1
,
2
. Similar to drug molecules, pollutants are typically metabolized in the body, which can change their carcinogenic potential and affect tissue distribution through altered toxicokinetics
3
. Although recent studies demonstrated that human-associated microorganisms can chemically convert a wide range of xenobiotics and influence the profile and tissue exposure of resulting metabolites
4
,
5
, the effect of microbial biotransformation on chemical-induced tumour development remains unclear. Here we show that the depletion of the gut microbiota affects the toxicokinetics of nitrosamines, which markedly reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice
6
,
7
. We causally linked this carcinogen biotransformation to specific gut bacterial isolates in vitro and in vivo using individualized bacterial culture collections and gnotobiotic mouse models, respectively. We tested gut communities from different human donors to demonstrate that microbial carcinogen metabolism varies between individuals and we showed that this metabolic activity applies to structurally related nitrosamine carcinogens. Altogether, these results indicate that gut microbiota carcinogen metabolism may be a contributing factor for chemical-induced carcinogenesis, which could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer.
A study links environmental nitrosamines to bladder cancer through their metabolism by specific commensal microorganisms occurring in the gastrointestinal tract of humans and mice.
Journal Article
Immune evasion before tumour invasion in early lung squamous carcinogenesis
Early detection and treatment are critical for improving the outcome of patients with cancer
1
. Understanding the largely uncharted biology of carcinogenesis requires deciphering molecular processes in premalignant lesions, and revealing the determinants of the intralesional immune reaction during cancer development. The adaptive immune response within tumours has previously been shown to be strongest at the earliest stage of carcinoma
2
,
3
. Here we show that immune activation and immune escape occur before tumour invasion, and reveal the relevant immune biomarkers of the pre-invasive stages of carcinogenesis in the lung. We used gene-expression profiling and multispectral imaging to analyse a dataset of 9 morphological stages of the development of lung squamous cell carcinoma, which includes 122 well-annotated biopsies from 77 patients. We identified evolutionary trajectories of cancer and immune pathways that comprise (1) a linear increase in proliferation and DNA repair from normal to cancerous tissue; (2) a transitory increase of metabolism and early immune sensing, through the activation of resident immune cells, in low-grade pre-invasive lesions; (3) the activation of immune responses and immune escape through immune checkpoints and suppressive interleukins from high-grade pre-invasive lesions; and, ultimately, (4) the activation of the epithelial–mesenchymal transition in the invasive stage of cancer. We propose that carcinogenesis in the lung involves a dynamic co-evolution of pre-invasive bronchial cells and the immune response. These findings highlight the need to develop immune biomarkers for early detection as well as immunotherapy-based chemopreventive approaches for individuals who are at high risk of developing lung cancer.
The immune response is modulated at a early stage of carcinogenesis, such that both immune activation and evasion precede tumour invasion.
Journal Article
The functional roles of exosomal long non-coding RNAs in cancer
Exosomes are extracellular membranous vesicles that are secreted by various cell types. Exosomes have become indispensable facilitators in the exchange of information between cells. More importantly, exosomes perform a crucial role in a variety of diseases including cancers. Long non-coding RNAs (lncRNAs) are over 200 nucleotides long transcripts that exhibit no or limited protein-coding potentials. LncRNAs are an emerging group of regulatory RNAs and can be selectively packaged into exosomes. Exosomal lncRNAs play a central role in carcinogenesis and cancer progression by modulating tumor growth, metastasis, angiogenesis and chemoresistance. Moreover, exosomal lncRNAs function as messengers in cell-to-cell communication, and thus remodel the tumor microenvironment. Their function relevance in cancer biology hints at the possibility of employing exosomal lncRNAs as promising, non-invasive biomarkers for further cancer therapy. In this review, we provide an overview of current research on the functional roles of exosomal lncRNAs in cancer and discuss their potential clinical applications as diagnostic biomarkers and therapeutic targets for cancers.
Journal Article
TSP50 Depends on Its Threonine Protease Activity and Its Interactions with TNF-alpha-Induced NF-kappaB for Its Role in Human Cervical Tumorigenesis
Testes-specific protease 50 (TSP50) has threonine activity and has homology to serine proteases. TSP50 protein, which is encoded by a possible proto-oncogene, is overexpressed in cervical tumor tissues. Through overexpression experiments using both TSP50 and a TSP50 mutant (TSP50 T310A), it is clear that this protein may play an important role in carcinogenesis and progression of cervical tumor. However, the mechanism underlying how TSP50 modulates cancer cell growth is still unclear. To examine the difference in TSP50 expression in cervical carcinoma tissues and in paracarcinoma tissues, we detected TSP50 mRNA and protein in ten paired tissues from patients with cervical cancer. To determine whether TSP50's threonine protease activity is crucial for its effects on tumor formation, we generated a mutant version of TSP50 (T310A). Via overexpression and silencing experiments, we identified a role for TSP50 in cell proliferation and migration. Furthermore, we examined the signaling pathway of TNF-[alpha]-induced NF[kappa]B activation to explain the mechanism by which TSP50 participates in tumorigenesis. Similarly, we found that all these effects could be abolished by the TSP50 T310A mutation. Our results suggest that the threonine 310 residue within TSP50 helps modulate its role in cervical tumorigenesis and indicates that TSP50's role in tumorigenesis may be dependent on its interaction with TNF-[alpha]-induced NF-[kappa]B.
Journal Article
Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states
Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis.
ERG
-negative tumor cells, compared to
ERG
-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.
The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.
Journal Article
Vasculogenic mimicry in carcinogenesis and clinical applications
Distinct from classical tumor angiogenesis, vasculogenic mimicry (VM) provides a blood supply for tumor cells independent of endothelial cells. VM has two distinct types, namely tubular type and patterned matrix type. VM is associated with high tumor grade, tumor progression, invasion, metastasis, and poor prognosis in patients with malignant tumors. Herein, we discuss the recent studies on the role of VM in tumor progression and the diverse mechanisms and signaling pathways that regulate VM in tumors. Furthermore, we also summarize the latest findings of non-coding RNAs, such as lncRNAs and miRNAs in VM formation. In addition, we review application of molecular imaging technologies in detection of VM in malignant tumors. Increasing evidence suggests that VM is significantly associated with poor overall survival in patients with malignant tumors and could be a potential therapeutic target.
Journal Article