Rudolf Virchow and Modern Aspects of Tumor Pathology

David, Heinz

doi:10.1016/s0344-0338(88)80138-9

Cited by 62 publications

(31 citation statements)

References 8 publications

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“…The connection between inflammation and the development of tumors has been known for a long time and was postulated by Rudolph Virchow as early as 1863 [33]. tissue of patients suffering from UC, CAC, and CRC, supporting our hypothesis that these cells play an important role in tumor growth.…”

Section: Discussionsupporting

confidence: 80%

RORγt⁺ hematopoietic cells are necessary for tumor cell proliferation during colitis‐associated tumorigenesis in mice

et al. 2015

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Colorectal cancer (CRC) is one of the most common tumor entities. In patients with inflammatory bowel diseases, the development of colitis-associated colon cancer is considered a dangerous long-term complication. IL-17A and the transcription factor retinoic acid receptor-related orphan receptor γt (RORγt) play fundamental roles in the pathogenesis of inflammatory bowel diseases; in human studies, we detected a dense infiltration of RORγt-dependent CD4+ IL17A + T helper (Th)17 cells in specimens of CRC, ulcerative colitis, and ulcerative colitis-associated colorectal cancer. However, the mechanistic role of RORγt + hematopoietic cells in colitis-associated tumorigenesis remains unclear. To investigate colitis-associated colon tumorigenesis, we conducted studies in the AOM+DSS mouse model that revealed the importance of RORγt for colon tumor progression. In the absence of RORγt-dependent Th17 lymphocytes, mice showed signs of intense chronic colitis, but developed significantly fewer macroscopic tumor nodules. The reduction of tumor development in RORγt −/− mice was not due to reduced colon tumor initiation. However, the proliferation rate of tumor cells was reduced in the absence of RORγt-dependent Th17 cells and tumor cells showed pronounced signs of senescence-associated epigenetic and lysosomal changes. These results indicate an important role for the immunological milieu in colitis-associated cancer, which is shaped in-part by RORγt-dependent Th17 lymphocytes that support CRC growth.Keywords: AOM+DSS r Colitis-associated colorectal cancer r Th17 cells r IL-17 r RORγtAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionColorectal cancer (CRC) is the third most common malignancy in humans, with high frequencies observed in North America, Correspondence: Dr. Stefan Fichtner-Feigl e-mail: stefan.fichtner@ukr.deEurope, and Australia [1]. The promotion of colorectal adenocarcinoma is an important long-term consequence of ulcerative colitis (UC) and Crohn's disease, the two main forms of human chronic inflammatory bowel diseases. These inflammation-associated cancers are generally characterized by a rapid clinical progression [2][3][4][5] Eur. J. Immunol. 2015. 45: 1667-1679 chronic disorders of the immune system and tumor development in various animal models, it is thought that chronic inflammation provides an immunological environment favoring tumor cell proliferation [6][7][8][9][10][11]. The nuclear hormone receptor retinoic acid receptor-related orphan receptor γt (RORγt) encoded by the RORc gene has been identified as the key transcription factor determining the differentiation of naïve T helper (Th) [20][21][22]. Currently, it is known that Th17 lymphocytes and their associated cytokines, in particular IL-17A, play a fundamental role in the pathogenesis of different autoimmune and chronic disorders such as inflammatory bowel diseases. While IL-17A is produced in the healthy gut, higher expression has been reported in inflamed intestin...

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Section: Discussionsupporting

confidence: 80%

RORγt⁺ hematopoietic cells are necessary for tumor cell proliferation during colitis‐associated tumorigenesis in mice

et al. 2015

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“…Among the proponents of this idea was Rudolf Virchow, who recognized elements of embryonic development in cancers. Virchow coined the term "teratoma" to describe tumors containing differentiated elements of the three embryonic germ layers and also suggested that cancers arise from embryo-like cells [1]. Lobstein and Cohnheim [2] also noted similarities between embryogenesis and the biology of cancer cells and put forward the hypothesis that tumorigenesis recapitulates aspects of development [2].…”

Section: Introductionmentioning

confidence: 99%

Embryonic mammary signature subsets are activated in Brca1 -/- and basal-like breast cancers

et al. 2013

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IntroductionCancer is often suggested to result from development gone awry. Links between normal embryonic development and cancer biology have been postulated, but no defined genetic basis has been established. We recently published the first transcriptomic analysis of embryonic mammary cell populations. Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents.MethodsWe defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells. We looked for activation of the embryonic mammary epithelial signature in mouse mammary tumors that formed in mice in which Brca1 had been conditionally deleted from the mammary epithelium and in human breast cancers to determine whether any genetic links exist between embryonic mammary cells and breast cancers.ResultsSmall subsets of the embryonic mammary epithelial signature were consistently activated in mouse Brca1-/- tumors and human basal-like breast cancers, which encoded predominantly transcriptional regulators, cell-cycle, and actin cytoskeleton components. Other embryonic gene subsets were found activated in non-basal-like tumor subtypes and repressed in basal-like tumors, including regulators of neuronal differentiation, transcription, and cell biosynthesis. Several embryonic genes showed significant upregulation in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and/or grade 3 breast cancers. Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors. By using RNA interference to silence SOX11 expression in breast cancer cells, we found evidence that SOX11 regulates breast cancer cell proliferation and cell survival.ConclusionsSpecific subsets of embryonic mammary genes, rather than the entire embryonic development transcriptomic program, are activated in tumorigenesis. Genes involved in embryonic mammary development are consistently upregulated in some breast cancers and warrant further investigation, potentially in drug-discovery research endeavors.

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“…Furthermore, this subgroup has the highest risk of developing lung cancer among smokers [5], [6]. It has been proposed that systemic inflammation may play an important pathogenic role in carcinogenesis [7], and whether individuals with emphysema have a different inflammatory profile is unknown. We therefore conducted this cross sectional study to investigate whether, in comparison to smokers without emphysema; patients with emphysema express a different plasma cytokine profile that could explain their increased risk for lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Smokers with CT Detected Emphysema and No Airway Obstruction Have Decreased Plasma Levels of EGF, IL-15, IL-8 and IL-1ra

et al. 2013

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RationaleLow-grade inflammation and emphysema have been shown to be associated with an increased risk of lung cancer. However, the systemic inflammatory response in patients with emphysema is still unknown.ObjectiveTo compare the plasma cytokine profiles in two groups of current or former smokers without airway obstruction: a control group of individuals without computed tomography (CT) detected emphysema vs. a study group of individuals with CT detected emphysema.MethodsSubjects underwent a chest CT, spirometry, and determination of EGF, IL-15, IL-1ra, IL-8, MCP-1, MIP-1β, TGFα, TNFα, and VEGF levels in plasma. Cytokine levels in each group were compared adjusting for confounding factors.Results160 current smokers and former smokers without airway obstruction participated in the study: 80 without emphysema and 80 subjects with emphysema. Adjusted group comparisons revealed significant reductions in EGF (−0.317, p = 0.01), IL-15 (−0.21, p = 0.01), IL-8 (−0.180, p = 0.02) and IL-1ra (−0.220, p = 0.03) in subjects with emphysema and normal spirometry.ConclusionsCurrent or former smokers expressing a well-defined disease characteristic such as emphysema, has a specific plasma cytokine profile. This includes a decrease of cytokines mainly implicated in activation of apoptosis or decrease of immunosurveillance. This information should be taken into account when evaluated patients with tobacco respiratory diseases.

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Rudolf Virchow and Modern Aspects of Tumor Pathology

Cited by 62 publications

References 8 publications

RORγt⁺ hematopoietic cells are necessary for tumor cell proliferation during colitis‐associated tumorigenesis in mice

RORγt⁺ hematopoietic cells are necessary for tumor cell proliferation during colitis‐associated tumorigenesis in mice

Embryonic mammary signature subsets are activated in Brca1 -/- and basal-like breast cancers

Smokers with CT Detected Emphysema and No Airway Obstruction Have Decreased Plasma Levels of EGF, IL-15, IL-8 and IL-1ra

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Rudolf Virchow and Modern Aspects of Tumor Pathology

Cited by 62 publications

References 8 publications

RORγt+ hematopoietic cells are necessary for tumor cell proliferation during colitis‐associated tumorigenesis in mice

RORγt+ hematopoietic cells are necessary for tumor cell proliferation during colitis‐associated tumorigenesis in mice

Embryonic mammary signature subsets are activated in Brca1 -/- and basal-like breast cancers

Smokers with CT Detected Emphysema and No Airway Obstruction Have Decreased Plasma Levels of EGF, IL-15, IL-8 and IL-1ra

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RORγt⁺ hematopoietic cells are necessary for tumor cell proliferation during colitis‐associated tumorigenesis in mice

RORγt⁺ hematopoietic cells are necessary for tumor cell proliferation during colitis‐associated tumorigenesis in mice