Translational values of tissue-resident memory T cells in chronic inflammation and cancer.

Mechanisms of Immune Signaling in Colitis-Associated Cancer

Cancer-associated systemic inflammation is strongly linked with poor disease outcome in cancer patients1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer cell-intrinsic mechanisms dictating the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Using a panel of 16 distinct genetically engineered mouse models (GEMMs) for breast cancer, we have uncovered a novel role for cancer cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, p53 loss in cancer cells induced secretion of Wnt ligands that stimulate IL-1β production by tumour-associated macrophages, which drives systemic inflammation. Pharmacological and genetic blockade of Wnt secretion in p53-null cancer cells reverses IL-1β expression by macrophages and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a novel mechanistic link between loss of p53 in cancer cells, Wnt ligand secretion and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for cancer patients.

Transcriptomic atlas of GNAT family members in pulmonary epithelia under pathological conditions using single‐cell and bulk cell sequencing

The American Association for Cancer Research has been the citadel for communicating research on chemical carcinogens for over a century. It therefore seems appropriate that a review of chemical carcinogenesis inaugurates a series of articles highlighting advances in understanding, treating, and preventing cancer.At the dawn of the 20th century, we had recognized that chemicals cause cancer, but we had not yet identified individual cancer-causing molecules, nor did we know their cellular targets. We clearly understood that carcinogenesis, at the cellular level, was predominantly an irreversible process. What we lacked was knowledge of the mechanisms by which chemicals cause cancer and the molecular changes that characterize tumor progression.We now are early in a century in which cancer is being investigated at the molecular level, and we have developed technologies that afford unprecedented power to delineate and manipulate altered pathways in cancer cells. Can we harness new insights and technologies to prevent or obliterate human cancers or delay their progression? Can we identify individuals who have a particularly high susceptibility to specific environmental carcinogens?The history of chemical carcinogenesis is punctuated by key epidemiologic observations and animal experiments that identified cancer-causing chemicals and that led to increasingly insightful experiments to establish molecular mechanisms and to reduction of human exposure. In 1914, Boveri (1) made key observations of chromosomal changes, including aneuploidy. His analysis of mitosis in frog cells and his extrapolation to human cancer is an early example of a basic research finding generating an important hypothesis (the somatic mutation hypothesis). The first experimental induction of cancer in rabbits exposed to coal tar was performed in Japan by Yamagiwa and Ichikawa (2) and was a confirmation of Pott's epidemiologic observation of scrotal cancer in chimney sweeps in the previous century (Fig. 1; ref. 3). Because coal tar is a complex mixture of chemicals, a search for specific chemical carcinogens was undertaken. British chemists, including Kennaway (4), took on this challenge and identified polycyclic aromatic hydrocarbons, for example, benzopryene, which was shown to be carcinogenic in mouse skin by Cook, Hewett, and Hieger in 1933 (5). The fact that benzopyrene and many other carcinogens were polyaromatic hydrocarbons lead the Millers (6) to postulate and verify that many chemical carcinogens required activation to electrophiles to form covalent adducts with cellular macromolecules. This in turn prompted Conney and the Millers (7) to identify microsomal enzymes (P450s) that activated many drugs and chemical carcinogens.The discovery of DNA as the genetic material by Avery, MacLeod, and McCarthy (8) and the description of the structure of DNA by Watson and Crick (9) indicated that DNA was the cellular target for activated chemical carcinogens and that mutations were key to understanding mechanisms of cancer. This led to defining the structure of the principal adducts in DNA by benzo(a)pyrene (10) and aflatoxin B1 (11). The concepts developed in investigating mechanisms of chemical carcinogenesis also led to discoveries that are relevant to other human conditions in addition to cancer, including atherosclerosis, cirrhosis, and aging.Global epidemiologic studies have indentified environmental and occupational chemicals as potential carcinogens. The most definitive epidemiologic studies have been those in which a small group is exposed to an inordinately large amount of a specific chemical, such as aniline dyes.Figure 1 illustrates exposure of individuals to residues from fossil fuel in chimneys, to tobacco smoke, and to fungi containing aflatoxin, and the identification of the responsible carcinogen(s). Active smoking and exposure to second-hand smoke are among the major causes of cancer mortality worldwide. Even after causative chemicals are identified, however, measurement of accumulated exposure of individuals in different environments remains an important challenge.The fact that genetic changes in individual cancer cells are essentially irreversible and that malignant changes are transmitted from one generation of cells to another strongly points to DNA as the critical cellular target modified by tobacco smoke and environmental chemicals. DNA damage by chemicals occurs randomly; the phenotypes of associated carcinogenic changes are determined by selection.Cancers caused by environmental agents frequently occur in tissues with the greatest surface exposure to the agents: lung, gastrointestinal tract, and skin. Recently, the study of chemical carcinogenesis has merged with studies on the molecular changes in cancer cells, thus generating biological markers to assess altered metabolic pathways and providing new targets for therapy. Although these are exciting areas, they may be peripheral to attacking the primary causes of the most common human cancers. As we catalog more and more mutations in cancer cells and more and more changes in transcription regulation, it becomes increasingly apparent that we need to understand what generates these changes. The fact that chemicals cause random changes in our genome immediately implies that our efforts need to be directed to quantifying these changes, reducing exposure, and developing approaches to chemoprevention.Chemical carcinogens cause genetic and epigenetic alterations in susceptible cells imparting a selective growth advantage; these cells can undergo clonal expansion, become genomically unstable, and become transformed into neoplastic cells. This classic view of carcinogenesis has its origin in experimental animal studies conducted in the mid 20th century. The first stage of carcinogenesis, tumor initiation, involves exposure of normal cells to chemical or physical carcinogens. These carcinogens cause genetic damage to DNA and other cellular macromolecules that provide initiated cells with both an altered responsiveness to their microenvironment and a proliferative advantage relative to the surrounding normal cells.Early in the field of chemical carcinogenesis, investigators recognized that perturbation of the normal microenvironment by physical means, such as wounding of mouse skin or partial hepatectomy in rodents (12, 13) or chemical agents, such as exposure of the mouse skin to certain phorbol esters (14), can drive clonal expansion of the initiated cells toward cancer. In the second stage, tumor promotion results in proliferation of the initiated cells to a greater extent than normal cells and enhances the probability of additional genetic damage, including endogenous mutations that accumulate in the expanding population. This classic view of two-stage carcinogenesis (14) has been conceptually important but also an oversimplification of our increasing understanding of the multiplicity of biological processes that are deregulated in cancer. In addition, an active debate continues on the relative contribution of procarcinogenic endogenous mechanisms—for example, free-radical–induced DNA damage (15), DNA depurination (16), DNA polymerase infidelity (17), and deamination of 5-methylycytosine (18)—compared with exposure to exogenous environmental carcinogens (19). The enhancement of carcinogens by epigenetic mechanisms such as halogenated organic chemicals and phytoestrogens (20), as well as the extrapolation of results from animal bioassays for identifying carcinogens to human cancer risk assessment, are also difficult to quantify (21). As discussed below, this debate is not merely an academic one, in that societal and regulatory decisions critical to public health are at issue. The identification of chemical carcinogens in the environment and occupational settings [benzo(a)pyrene and tobacco-specific nitrosamines in cigarette smoke, aflatoxin B1 (AFB1) residues from fossil fuel, vinyl chloride, and benzene] has led to regulations that have reduced the incidence of cancer.A timeline of selected experimental advances in chemical carcinogenesis that have important implications is presented in Fig. 2. First, the selected advances reflect the judgment of the authors and consultants, and remain to be modified by the readers, and, ultimately, by history. Second, the timeline shows the progression of results; an important observation generates new hypotheses that are tested by experiments with increasing mechanistic focus. Third, the timeline is punctuated with three important molecular discoveries (DNA structure, DNA sequence, and the PCR) that refocused experiments in chemical carcinogenesis (9, 22, 23). Fourth, many technological advances have allowed conceptual ideas to be experimentally tested, including the sensitive detection of chemical carcinogens by high-pressure liquid chromatography (24) and mass spectrometry (25), detection of DNA adducts by postlabeling (26) and by specific antibodies (27), transcriptional profiling by arrays (28, 29), and quantitation of mutagenicity of carcinogens using bacterial genetics (19).In the first half of the 20th century, the experimental focus was on identifying chemical carcinogens in complex mixtures, and on determining their metabolism and cellular targets. With the recognition that genes are encoded in DNA (9) and that DNA is transferred from one cellular generation to the next (30), research rapidly focused on the interaction of activated chemical carcinogens with DNA and on mutations that result from DNA alterations as well as the identification of key mutated (31) or deregulated genes including oncogenes and tumor suppressor genes (32). Underlying these studies was the expectation that delineation of mutated genes would identify them as specific targets for chemotherapy. The expectation that targeting individual mutated or rearranged gene products would be efficacious for cancer treatment has thus far been verified in only a limited number of situations, such as the use of imatinib for chronic myelogenous leukemia (33).The experimental landmarks highlighted in Fig. 2 frequently generated new experiments, and this progression has foretold some of our key concepts on the mechanisms of chemical carcinogenesis. An overriding concept has emerged that links DNA damage by reactive chemicals, the production of mutations by unrepaired DNA adducts, and the selection of cells harboring mutated genes that characterize the malignant phenotype. Studies on arylhydroxylamines provided a paradigm for tracing the metabolism of carcinogens to chemically reactive electrophiles that covalently bind to DNA. 2-Acetylaminofluorene (AAF) is metabolically activated by liver microsomal mixed–function oxygenases to N-hydroxy- and then to N-sulf oxy-AAF, a strong electrophile that forms covalent adducts with guanine moieties in DNA (34). AAF is not mutagenic in bacterial assays, whereas N-hydroxy-AAF is highly carcinogenic (34). N-hydroxy-AAF is rendered inactive by the formation of a glucuronide in the liver that is transported to the bladder and excreted (35). Unfortunately, it is subjected to acid hydrolysis in the bladder to yield active N-hydroxy-AAF, which is associated with human bladder cancer. Thus, the activation and detoxification of a chemical carcinogen in specific cells or tissues can be a major factor in determining tissue and host specificity.The testing of certain concepts in chemical carcinogenesis awaited the development of new technologies. For example, the concept of somatic mutations in cancer (1, 36) preceded by 40 years the establishment of DNA as the genetic material (8) and by 63 years the development of DNA sequencing methods (23) that directly showed clonal mutations in human cancer cells. Also, the mutator phenotype hypothesis formulated in 1974 (17) has been only recently experimentally verified (37).Many hypotheses are still under active investigation. These include the potential importance of carcinogen-protein interactions (38), carcinogen-induced reversion to stem cell–like phenotypes (39), inherited changes in gene expression (40, 41), direct action of nongenotoxic chemicals (42), and targeted interactions of carcinogens with specific genes such as TP53 (43–45). Other concepts focus on carcinogenesis mediated by RNA damage (46), RNA-templated DNA repair (47), specific metastasis genes (48, 49), and sequential clonal lineage pathways in cancer (50, 51).Emerging hypothesis such as anticarcinogens (52), overlapping pathways to malignancy (53), coordinated changes in gene expression (54), epigenetic silencing by chemical carcinogens (40, 55, 56), and oncogene addiction (57) are just beginning to be explored. Finally, there are concepts for which quantitation is lacking, yet have stood the test of time based on their inherent significance; these include the importance of anaerobic metabolism by tumors (58, 59) and the initiation of tumorigenesis by the generation of oxygen-reactive species (15).Although establishing DNA as the genetic material provided a structure that faithfully can be duplicated during each cell division, it rapidly became apparent that DNA was also subject to direct modification by X-rays (60), alkylating agents (61), and by an increasing number of environmental chemicals (62, 63). Changes in DNA by many chemical carcinogens are indirect; they first require activation by P-450 aryl hydroxylases into electrophiles to form covalent adducts with DNA and with other cellular macromolecules (64, 65). Many normally generated reactive molecules that are intermediates in metabolism modify many cellular molecules including DNA and therefore are mutagens and carcinogens. However, not all mutagens seem to be carcinogens. What was unanticipated was the magnitude of DNA modification by normal cellular processes in the absence of exposure to environmental mutagens (66, 67).The lability of DNA in an aqueous environment was first quantified by Lindahl and Nyberg, who measured the rates of depurination (16) and deamination (18) in solution under different conditions and extrapolated these results to those predicted to be present in human cells. They calculated that each normal cell could undergo >10,000 DNA damaging events per day. Endogenously generated modifications of DNA include methylation by S-adenosylmethione, modification by lipid peroxidation products, chlorination, glycosylation, oxidation, and nitrosylation (66–71). Reactive oxygen and nitrogen species are particularly relevant because the activated species are generated by host cells, and the process of resynthesis results in the replacement of >50,000 nucleotides per cell per day (68). To maintain our genomes, we have evolved a network of DNA repair pathways to excise altered residues from DNA (Fig. 3). A major consideration is the relative contribution of environmental and endogenous DNA damage to carcinogenesis. DNA damage by environmental agents would have to be extensive and exceed that produced by normal endogenous reactive chemicals to be a major contributor to mutations and cancer. This consideration underlines the difficulty in extrapolating risk of exposure to that which would occur at very low doses of carcinogens.Human cells possess an armamentarium of mechanisms for DNA repair that counter the extensiveness of DNA damage caused both by endogenous and environmental chemicals. These mechanisms include base excision repair (BER) that removes products of alkylation and oxidation (72–74); nucleotide excision repair (NER) that excises oligonucleotide segments containing larger adducts (75); mismatch repair that scans DNA immediately after polymerization for misincorporation by DNA polymerases (76); and oxidative demethylation (77), transcription-coupled repair (TCR) that preferentially repairs lesions that block transcription (78); double-strand break repair and recombination that avoids errors by copying the opposite DNA strand (79); as well as mechanisms for the repair of cross-links between strands (80, 81) that yet need to be established.Most DNA lesions are subject to repair by more than one pathway. As a result, only a minute fraction of DNA lesions escapes correction are present at the time of DNA replication and can direct the incorporation of noncomplementary nucleotides resulting in mutation (Fig. 3). Unrepaired DNA lesions initiate mutagenesis by stalling DNA replication forks or are copied over by error-prone trans-lesion DNA polymerases (82–84). Alternatively, incomplete DNA repair can result in the accumulation of mutations and mutagenic lesions, such as abasic sites (85).Damage to DNA by chemical carcinogens activates checkpoint signaling pathways leading to cell cycle arrest and allows time for DNA repair processes. In the absence of repair, cells can use special DNA polymerases that copy past DNA adducts (86, 87), or undergo apoptosis by signaling the recruitment of immunologic and inflammatory host defense mechanisms. The demonstration that each methylcholanthrene-induced tumor has a unique antigenic signature provided one of the earliest glimpses into the stochastic nature of cellular responses to carcinogens (88). The immunologic and inflammatory responses facilitate not only engulfment and clearance of damaged cells but also the resulting generation of reactive oxygen (89) and nitrogen radicals (90) that further damage cellular DNA.The concept that chronic inflammation can result in cancer is supported by Virchow's (91) histologic observation of inflammatory lymphocytes infiltrating tumors. Inflammation accompanying the "painting" of coal tar was described by Japanese pathologists in the earliest experimental study of chemical carcinogenesis (2). The classic tumor promoter, croton oil, and its most active ingredient, 12-O-tetradecanoylphorbol-13-acetate, are potent inflammatory agents. In addition to studies of "two-stage" skin carcinogenesis, other animal models have shown the synergistic interaction of chemical carcinogens with proinflammatory agents; for example, respiratory infection with influenza virus synergistically increases the lung cancer response in rats to a carcinogenic N-nitrosamine (92).Chronic inflammation can have a strong inherited basis, e.g. hemochromatosis, or can be acquired from infection by viruses, bacteria, or parasites or be associated with metabolic or physical conditions (93). Obesity has been considered to be a chronic inflammatory condition associated with multiple types of human cancer (94); gastric acid reflux causes chronic inflammation and can progress to Barrett's-associated esophageal adenocarcinoma (95); and colitis can progress to colon cancer (96, 97). Recent advances have begun to uncover the underlying mechanisms of the association between chronic inflammation and cancer.The identification of specific genes by allelic replacements and "knockouts" has facilitated the delineation of complex immune response networks that govern cellular responses to chemical carcinogens. The innate immune system is the first line of defense against pathogenic microorganisms and toxins and responds by generating free radicals, inflammatory cytokines, and the activation of the complement cascade (93, 98). In addition to reactive oxygen species, the past two decades have shown the significance of nitrogen-based free radicals, including nitric oxide and its derivatives (90, 93). The concentration and length of exposure can determine the seemingly paradoxical procarcinogenic and anticarcinogenic activities of free As be discussed in another in the chronic activation of the innate immune system is procarcinogenic and immune system is anticarcinogenic there is a to from an individual is exposed to a carcinogen to the detection of a For most there is an in cancer incidence as a of that tumor progression in a series of sequential This process has been most in colon cancer, with the progression from to to and to metastasis of cancers at different from to a sequential of mutations and genome mutations in DNA activation of of on and of This concept of sequential mutations has been by new including the of somatic mutations in and colon cancers and the demonstration that only a small fraction of colon cancers the three most frequently identified mutations this may identify potential not cancers a mutator a more stochastic cancer cell in a tumor of different and yet only a small of cells preferentially during to random mutations that a selective advantage for this concept is the demonstration that the of mutations in human cancers is greater than that in normal tissues in cell and adenocarcinoma of the colon The genetic of cancer cells produced by mutator mutations increases the that a tumor many cells to and is with the of of research in chemical carcinogenesis have provided a for the analysis of adducts and somatic mutations in as of carcinogen exposure. A paradigm for between of carcinogens exposure and a cancer risk is shown in Fig. a is a example of an environmental chemical carcinogen that has been using this a polycyclic aromatic (53), an aromatic and a tobacco-specific N-nitrosamine are other key epidemiologic studies a association between exposure and the incidence of studies of in multiple animal species, chemical and analysis of the identification of DNA adducts, and of mutagenic the for and to as a human carcinogen from these experimental animal and studies were then and to assess exposure and biological in studies conducted in of high exposure and high incidence of such as and The were and to the of the that is a human The between and was further by the association between exposure and a specific mutation in the nucleotide of of the tumor suppressor gene in In from and The a synergistic interaction between exposure or and of virus infection in the risk of was remain to be For example, the molecular of the synergistic interaction between and is still the and oxidative of to the gene incorporation in the genome of their of by advances in molecular are and they increasingly are being to understanding the interaction of chemical carcinogens with cellular and of DNA has facilitated the identification of specific genes mutated in human cancers. including mass to carcinogen with unprecedented and spectrometry is being with mutagenesis to specific alterations in DNA of the human genome and the identification of DNA enzymes the field of molecular in on individual susceptibility to carcinogens. analysis of carcinogen-induced alterations in the expression of both and the are that can molecules of carcinogens in cells, random mutations in individual cells, analysis of the of molecules and and and genetic to delineate complex pathways in cells. Underlying this progress in understanding chemical carcinogenesis is a cascade of advances in molecular that it to quantify DNA damage by chemical agents, and changes in gene the structure of DNA and the cell including carcinogenesis. in detection of DNA damage, including postlabeling of DNA (27), and mass spectrometry (25), have allowed the detection of a altered base in nucleotides using human DNA. This can be to DNA or RNA in a cell in cell including and it to assess changes in RNA and expression during carcinogenesis. these technologies it increasingly to pathways in cancer cells from to to to have made in identifying chemical carcinogens and their mechanisms of We have increasingly focused on DNA as a the fact at the cellular level, cancer is an inherited a cancer, a cancer. The efforts to chemicals as potential or human carcinogens are not but in most are in The need to identify chemical carcinogens in of human exposure and epidemiologic is on mechanistic and knowledge of and among animal species is a For example, the of in the by a not to be relevant to carcinogenesis, is initiated by epidemiologic verified by animal experiments, and by mechanistic and studies The between carcinogen exposure and the induction of cancer continues to be a of and public debate The of a is a in the of public health that to be as mechanistic accumulate in the field of chemical carcinogenesis has a history of that of cancer cancer risk assessment, public health and and occupational causes of cancer. The concepts of interactions and in the molecular of human cancer risk were generated by the of chemical carcinogenesis, cellular and molecular and cancer genetic in DNA repair and enzymes are of an inherited of in cancer susceptibility of the of cancer risk and detection are based on the knowledge of chemical carcinogenesis, including adducts, somatic and mutation carcinogen exposure and DNA with interactions can have synergistic for example, and in carcinogenesis. models of chemical carcinogenesis to a critical in the field of cancer and in our understanding the mechanisms of cancer and the of in in the field of chemical carcinogenesis remain to be stem cells mutated by chemical carcinogens and become of human chemical carcinogens epigenetic changes during These and other many to be formulated by to investigators in chemical carcinogenesis our understanding of carcinogenesis, and, as a result, cancer and potential of were Cancer and and by The Research of the Cancer for Cancer Research of of this were in by the of This therefore be in with to this selection of the major events in this review of the field are the primary of the with the of the The authors for many of which are of importance to the field of chemical carcinogenesis. We on this subject We for Fig. of chimney and for Fig. and of smoking and aflatoxin, and and for their critical

The majority of the human genome (>70%) contains non-coding DNA consisting of retrotransposable elements (RTE), such as LINE-1, SINE/Alu elements, human endogenous retroviruses (HERV), and satellite repeat DNA (Hsat2 and Hsat3). The expression of these elements is suppressed in normal adult tissues but are abnormally expressed in many cancers. Another key mechanism in cancer initiation and progression is the release of tumor-derived extracellular vesicles (EV) that are long-distance communication vehicles propagating signals from tumors inducing metabolic changes, immune dysregulation and promoting metastases across the body. Our work has uncovered a link between RTE, HERV and Hsat expression in cancer and EV in driving tumor progression and immune dysregulation. W hole transcriptome sequencing of EV derived from several different cancer cell lines and patient samples, including Ewing sarcoma, osteosarcoma, prostate, pancreatic, and breast cancer found that RTE, HERV and Hsat2,3 transcripts are highly enriched in EV versus coding region transcripts and in much higher abundance than in the tumor cell themselves. Tumor-derived EV contained dsRNA, dsDNA and RNA:DNA hybrids from these non-coding regions. Plasma EV isolated from both metastatic and non-metastatic patients also showed an enrichment of these RTE, HERV and Hsat2,3 elements and clearly differentiated healthy, normal donor EV that had little or no detectable signal. Evidence of local dissemination of these non-coding elements in EV was also found in vivo in tumor xenografts that showed transfer of Hsat2,3 transcripts into the murine stroma that naturally lack these satellite repeats. Treatment of fibroblasts and myeloid cells with tumor-derived EV triggered innate immune responses via type I IFN and pro-inflammatory cytokines, including IL-1beta, IL-6, IL-8, and TNFalpha owing to the pathogen-like nucleic acid sequences (viral mimicry) of these elements. These EV-induced chronic inflammatory effects were mainly induced through the cGAS-STING nucleic acid sensing pathway. Evidence of DNA damage in stromal fibroblasts and induced senescence was also found as a result of EV treatment. A key element of RTE is the expression of LINE-1 and HERV derived reverse transcriptase (RT) that propagates the action of RTE via RNA:DNA hybrids, dsDNA and retrotransposition in the genome. In a spontaneous estradiol-driven breast cancer model in ACI rats, long-term treatment with an HIV RT inhibitor (lamivudine/3TC) inhibited breast tumor development associated with reduced RTE activation in the mammary gland and in circulating immune cells as well as reduced chronic systemic innate inflammation. Our results suggest that RTE, HERV and Hsat activation, together with their local and systemic dissemination in EV plays an important role in cancer initiation and progression associated with chronic inflammation. We also suggest that abnormal dissemination of these activated non-coding elements in EV may also play a role in "inflammaging" facilitating not only cancer but also other chronic diseases. Citation Format: Laszlo Radvanyi, Valentina Evdokimova, Peter Ruzanov, Zhenbo Zhang, Poul Sorenson, Hendrik Gassmann, Stefan Burdach, Lincoln D. Stein. Dissemination of retrotransposable elements from the non-coding genome in tumor-derived extracellular vesicles target stromal and immune cells to induce local and systemic inflammation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C012.

Background: The mechanisms underlying low intensity ultrasound (LIUS) mediated suppression of inflammation and tumorigenesis remain poorly determined.Methods: We used microarray datasets from NCBI GEO Dataset databases and conducted a comprehensive data mining analyses, where we studied the gene expression of 299 cell death regulators that regulate 13 different cell death types (cell death regulatome) in cells treated with LIUS.Results: We made the following findings: (1) LIUS exerts a profound effect on the expression of cell death regulatome in cancer cells and non-cancer cells. Of note, LIUS has the tendency to downregulate the gene expression of cell death regulators in non-cancer cells. Most of the cell death regulator genes downregulated by LIUS in non-cancer cells are responsible for mediating inflammatory signaling pathways; (2) LIUS activates different cell death transcription factors in cancer and non-cancer cells. Transcription factors TP-53 and SRF- were induced by LIUS exposure in cancer cells and non-cancer cells, respectively; (3) As two well-accepted mechanisms of LIUS, mild hyperthermia and oscillatory shear stress induce changes in the expression of cell death regulators, therefore, may be responsible for inducing LIUS mediated changes in gene expression patterns of cell death regulators in cells; (4) LIUS exposure may change the redox status of the cells. LIUS may induce more of antioxidant effects in non-cancer cells compared to cancer cells; and (5) The genes modulated by LIUS in cancer cells have distinct chromatin long range interaction (CLRI) patterns to that of non-cancer cells.Conclusions: Our analysis suggests novel molecular mechanisms that may be utilized by LIUS to induce tumor suppression and inflammation inhibition. Our findings may lead to development of new treatment protocols for cancers and chronic inflammation.

Loss of 15-Hydroxyprostaglandin Dehydrogenase Expression Contributes to Bladder Cancer Progression

Axl Receptor Axis: A New Therapeutic Target in Lung Cancer

31 Loss of P53 drives systemic neutrophilic inflammation in breast cancer

Regulation of Gastric Carcinogenesis by InflammatoryCytokines.

Although chronic inflammation increases the risk of carcinogenesis, there have been few reports of genome-wide screening for chromosomal alterations and DNA damage, such as mutations and strand breaks, induced by chronic inflammation. This study utilized high-resolution comparative genomic hybridization to detect copy number variations (CNVs) between normal and cancerous lung cells treated with tumor necrosis factor-alpha (TNF-α) for 24 weeks to induce chronic inflammation. Ingenuity Pathway Analysis was used to analyze the functions of genes located at the common CNV regions that were induced by chronic inflammation. The results shown that TNF-α induced more CNVs in normal lung cells than in cancerous lung cells. Moreover, Ingenuity Pathway Analysis was used to analyze the function of genes located at the common CNV regions get involved in cancer progression, DNA repair and inflammatory disease. In conclusion, chronic inflammation might be one of a set of factors which transform normal lung cells into tumor cells.

Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co-culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype.

BackgroundWe explored if known risk factors for pancreatic cancer such as type II diabetes and chronic inflammation, influence the pathophysiology of an established primary tumor in the pancreas and if administration of metformin has an impact on tumor growth.MethodsPancreatic carcinomas were assessed in a syngeneic orthotopic pancreas adenocarcinoma model after injection of 6606PDA cells in the pancreas head of either B6.V-Lepob/ob mice exhibiting a type II diabetes-like syndrome or normoglycemic mice. Chronic pancreatitis was then induced by repetitive administration of cerulein. Cell proliferation, cell death, inflammation and the expression of cancer stem cell markers within the carcinomas was evaluated by immunohistochemistry. In addition, the impact of the antidiabetic drug, metformin, on the pathophysiology of the tumor was assessed.ResultsDiabetic mice developed pancreatic ductal adenocarcinomas with significantly increased tumor weight when compared to normoglycemic littermates. Diabetes caused increased proliferation of cancer cells, but did not inhibit cancer cell necrosis or apoptosis. Diabetes also reduced the number of Aldh1 expressing cancer cells and moderately decreased the number of tumor infiltrating chloracetate esterase positive granulocytes. The administration of metformin reduced tumor weight as well as cancer cell proliferation. Chronic pancreatitis significantly diminished the pancreas weight and increased lipase activity in the blood, but only moderately increased tumor weight.ConclusionWe conclude that diabetes type II has a fundamental influence on pancreatic ductal adenocarcinoma by stimulating cancer cell proliferation, while metformin inhibits cancer cell proliferation. Chronic inflammation had only a minor effect on the pathophysiology of an established adenocarcinoma.

BackgroundPatients with cancer develop endothelial dysfunction and subsequently display a higher risk of cardiovascular events. The aim of the present work was to examine changes in nitric oxide (NO)- and prostacyclin (PGI2)-dependent endothelial function in the systemic conduit artery (aorta), in relation to the formation of lung metastases and to local and systemic inflammation in a murine orthotopic model of metastatic breast cancer.MethodsBALB/c female mice were orthotopically inoculated with 4T1 breast cancer cells. Development of lung metastases, lung inflammation, changes in blood count, systemic inflammatory response (e.g. SAA, SAP and IL-6), as well as changes in NO- and PGI2-dependent endothelial function in the aorta, were examined 2, 4, 5 and 6 weeks following cancer cell transplantation.ResultsAs early as 2 weeks following transplantation of breast cancer cells, in the early metastatic stage, lungs displayed histopathological signs of inflammation, NO production was impaired and nitrosylhemoglobin concentration in plasma was decreased. After 4 to 6 weeks, along with metastatic development, progressive leukocytosis and systemic inflammation (as seen through increased SAA, SAP, haptoglobin and IL-6 plasma concentrations) were observed. Six weeks following cancer cell inoculation, but not earlier, endothelial dysfunction in aorta was detected; this involved a decrease in basal NO production and a decrease in NO-dependent vasodilatation, that was associated with a compensatory increase in cyclooxygenase-2 (COX-2)- derived PGI2 production.ConclusionsIn 4 T1 metastatic breast cancer in mice early pulmonary metastasis was correlated with lung inflammation, with an early decrease in pulmonary as well as systemic NO availability. Late metastasis was associated with robust, cancer-related, systemic inflammation and impairment of NO-dependent endothelial function in the aorta that was associated with compensatory upregulation of the COX-2-derived PGI2 pathway.

Inflammation and Colon Cancer