Ultrastructural observations of lung neoplasms induced in the strain A/J mouse by benzo(a)pyrene and ethylnitrosourea

The current literature regarding the histogenesis of mouse lung adenomas suggests two alternative cells of origin for these tumors. The Type II pneumocyte was accepted by most investigators as the cell which proliferated either spontaneously or by chemical induction, until Kauffman and co-workers reported histologic and ultrastructural features of a Clara cell adenoma, and indicated that in Swiss mice, 63% of all chemically induced tumors appeared to be Clara cell derived. Ward et al. using immunocytochemical techniques have demonstrated that all lung adenomas they tested in B6C3F1, BALB, and A strain mice appear to be of alveolar cell origin. It has also been reported that up to 70% of ethylnitrosourea induced adenomas can be characterized as Clara cell based on histochemical staining for nitroblue tetrazolium reductase.Histological investigation of lung tumors arising in Strain A/J mice from bioassays of thirteen chemicals demonstrates a variable growth pattern.

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TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

10.31234/osf.io/v24zc ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Cancer Progression ◽

Hypoxia Inducible Factor ◽

Tumor Hypoxia ◽

Human Lung Cancer ◽

Regulatory Subunit ◽

Patients With Cancer ◽

Hypoxia Inducible Factor 1 ◽

Chemically Induced ◽

Induced Tumors ◽

Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activationare associated with cancer progression. Here, we demonstrate thatthe transcription factor TAp73 opposes HIF-1 activity through anontranscriptional mechanism, thus affecting tumor angiogenesis.TAp73-deficient mice have an increased incidence of spontaneousand chemically induced tumors that also display enhanced vascularization.Mechanistically, TAp73 interacts with the regulatory subunit(α) of HIF-1 and recruits mouse double minute 2 homolog intothe protein complex, thus promoting HIF-1α polyubiquitination andconsequent proteasomal degradation in an oxygen-independentmanner. In human lung cancer datasets, TAp73 strongly predictsgood patient prognosis, and its expression is associated with lowHIF-1 activation and angiogenesis. Our findings, supported by invivo and clinical evidence, demonstrate a mechanism for oxygenindependentHIF-1 regulation, which has important implicationsfor individualizing therapies in patients with cancer.

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Methylene chloride: acute mouse lung morphology, biochemistry and clara cell culture characteristics

Respiratory Medicine ◽

10.1016/s0954-6111(05)80297-5 ◽

1993 ◽

Vol 87 (8) ◽

pp. 653

Author(s):

J.R. Foster ◽

T. Green ◽

L.L. Smith ◽

S. Tittensor ◽

I. Wyatt

Keyword(s):

Cell Culture ◽

Methylene Chloride ◽

Clara Cell ◽

Mouse Lung ◽

Lung Morphology ◽

Culture Characteristics

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Immunolocalization of Sonic Hedgehog (Shh) in Developing Mouse Lung

Journal of Histochemistry & Cytochemistry ◽

10.1177/002215540104901213 ◽

2001 ◽

Vol 49 (12) ◽

pp. 1593-1603 ◽

Cited By ~ 49

Author(s):

Leigh-Anne D. Miller ◽

Susan E. Wert ◽

Jeffrey A. Whitsett

Keyword(s):

Epithelial Cells ◽

Sonic Hedgehog ◽

Normal Development ◽

Clara Cell ◽

Mouse Lung ◽

Lung Hypoplasia ◽

Hepatocyte Nuclear Factor ◽

Clara Cells ◽

Lung Morphogenesis ◽

Conducting Airways

Expression of sonic hedgehog (Shh) is required for normal development of the lung during embryogenesis. Loss of Shh expression in mice results in tracheoesophageal fistula, lung hypoplasia, and abnormal lung lobulation. To determine whether Shh may play a role later in lung morphogenesis, immunostaining for Shh was performed in mouse lung from embryonic day (E) 10.5 to postnatal day (PD) 24. Shh was detected in the distal epithelium of the developing mouse lung from E10.5 to E16.5. From E16.5 until PD15, Shh was present in epithelial cells in both the peripheral and conducting airways. Although all cells of the developing epithelium uniformly expressed Shh at E10.5, Shh expression was restricted to subsets of epithelial cells by E16.5. Between E16.5 and PD15, non-uniform Shh staining of epithelial cells was observed in the conducting airways in a pattern consistent with the distribution of non-ciliated bronchiolar cells (i.e., Clara cells) and the Clara cell marker CCSP. Shh did not co-localize with hepatocyte nuclear factor/forkhead homologue-4 (HFH-4), β-tubulin, or with the presence of cilia. These results support the concept that Shh plays a distinct regulatory role in the lung later in morphogenesis, when it may influence formation or cytodifferentiation of the conducting airways.

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The effects of phenethyl isothiocyanate on benzo[a]pyrene-induced tumors and DNA adducts in AJ mouse lung

Cancer Letters ◽

10.1016/0304-3835(93)90094-p ◽

1993 ◽

Vol 71 (1-3) ◽

pp. 35-42 ◽

Cited By ~ 32

Author(s):

Gabriela Adam-Rodwell ◽

Mark A. Morse ◽

Gary D. Stoner

Keyword(s):

Dna Adducts ◽

Mouse Lung ◽

Phenethyl Isothiocyanate ◽

Induced Tumors

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Immunotherapy of Chemically-Induced Tumors in the Hamster Cheek Pouch with Dinitrochlorobenzene

Journal of Dental Research ◽

10.1177/00220345780570041601 ◽

1978 ◽

Vol 57 (4) ◽

pp. 625-630 ◽

Cited By ~ 2

Author(s):

Martin Marshack ◽

Patrick Toto ◽

Ronald Kerman

Keyword(s):

Defense Mechanisms ◽

Immune Defense ◽

Lymphoid Cells ◽

Cheek Pouch ◽

Hamster Cheek Pouch ◽

Time Intervals ◽

Tumor Induction ◽

Chemically Induced ◽

Induced Tumors ◽

Tumor Area

Immune stimulation with an agent such as dinitrochlorobenzene (DNCB) may delay chemcal carcinogenesis. Dimethylbenzanthracene (DMBA) was used to chemically induce tumors in the hamster buccal pouch. Hamsters were studied for the effect of DNCB sensitization in the buccal pouch prior to or after DMBA tumor induction. At appropriate time intervals the hamsters were sacrificed and each cheek pouch was examined histologically for the development of DMBA-induced tumors and for the presence of lymphoid cells infiltrating the tumor site. The results show that DNCB immunotherapy or immunoprophylaxis prior to or following DMBA tumor induction can alter the type of tumor produced and stimulate an infiltration of lymphoid cells into the tumor area probably invoking immune defense mechanisms.

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Studies on chemically induced tumors in rats: I. Heterogeneity of tumor cells and establishment of syngeneic, tumor-specific cytotoxic T cell clones

Cellular and Molecular Life Sciences ◽

10.1007/bf01960619 ◽

1983 ◽

Vol 39 (1) ◽

pp. 39-47 ◽

Cited By ~ 2

Author(s):

H. Binz ◽

M. Fenner ◽

H. Wigzell

Keyword(s):

T Cell ◽

Tumor Cells ◽

Cytotoxic T Cell ◽

T Cell Clones ◽

Syngeneic Tumor ◽

Cell Clones ◽

Chemically Induced ◽

Induced Tumors

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Profiles of chemically-induced tumors in rodents: quantitative relationships

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/s0027-5107(98)00161-4 ◽

1998 ◽

Vol 421 (1) ◽

pp. 93-107 ◽

Cited By ~ 5

Author(s):

Romualdo Benigni ◽

Anna Pino

Keyword(s):

Chemically Induced ◽

Induced Tumors

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Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development

Development ◽

10.1242/dev.126.18.4005 ◽

1999 ◽

Vol 126 (18) ◽

pp. 4005-4015 ◽

Cited By ~ 14

Author(s):

M. Weaver ◽

J.M. Yingling ◽

N.R. Dunn ◽

S. Bellusci ◽

B.L. Hogan

Keyword(s):

Cell Types ◽

Surfactant Protein ◽

Bmp Signaling ◽

Dominant Negative ◽

Clara Cell ◽

Mouse Lung ◽

Marker Genes ◽

Distal Marker ◽

Morphogenetic Protein

In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693–1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program.

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