Cellular tumorigenicity in nude mice: Correlation with cell growth in semi-solid medium

doi:10.1016/0092-8674(74)90050-6

Cell

Volume 3, Issue 4, December 1974, Pages 355-359

https://doi.org/10.1016/0092-8674(74)90050-6 Get rights and content

Abstract

Cultured cells derived from either normal or malignant tissues of several species have been tested by injection into the immune-deficient nude mouse in order to determine the cellular properties which are associated with tumorigenicity in vivo. Results show that one in vitro property consistently correlated with neoplastic growth in nude mice is the ability of the cell to form spherical colonies in a semi-solid growth medium such as methyl cellulose suspension. Cellular tumorigenicity is not determined solely by the malignancy of the tissue of origin, since cells derived from nonmalignant tissues become tumorigenic when they are no longer anchorage dependent for growth. In addition, acquisition of infinite growth potential in heteropioid cell lines is not in itself sufficient to confer tumorigenic capacity on the cells. These results suggest that the degree of cell growth in methyl cellulose is a useful parameter in vitro for predicting tumorigenicity in the animal, and also demonstrate the potential usefulness of the nude mouse for analysis of cellular malignancy irrespective of the tissue or species of origin.

References (29)

L. Hayflick et al.
Exp. Cell Res.
(1961)
I. MacPherson et al.
Virology
(1964)
I. MacPherson et al.
Virology
(1962)
R. Risser et al.
Virol.
(1974)
H. Temin et al.
Virology
(1958)
S.A. Aaronson et al.
Science
(1968)
L. Berman et al.
T.T. Chen et al.
Int. J. Cancer
(1969)
R. Dulbecco
Nature
(1970)
V.H. Freedman et al.
Genetics
(1974)

G.O. Gey et al.

Cancer Res.

(1952)

B.C. Giovanella et al.

J. Nat. Cancer Inst.

(1974)

R.J. Klebe et al.

J. Cell Biol.

(1970)

J.W. Littlefield

Science

(1964)

Cited by (746)

Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation
2022, Mitochondrion
The correlation between mitochondrial function and oncogenesis is complex and is not fully understood. Here we determine the importance of mitochondrial-linked pyrimidine synthesis for the aggressiveness of cancer cells. The enzyme dihydroorotate dehydrogenase (DHODH) links oxidative phosphorylation to de novo synthesis of pyrimidines. We demonstrate that an inhibition of DHODH results in a respiration-independent significant increase of anchorage-independent growth but does not affect DNA repair ability. Instead, we show an autophagy-independent increase of lysosomes. The results of this study suggest that inhibition of mitochondrial-linked pyrimidine synthesis in cancer cells results in a more aggressive tumor phenotype.
Cell death pathways and viruses: Role of microRNAs
2021, Molecular Therapy Nucleic Acids
Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions, particularly critical pathways for cell death, by affecting various intracellular mediators. MicroRNAs (miRNAs) are a major example of these mediators because they are involved in many (if not most) cellular mechanisms. Virus-regulated miRNAs have been implicated in three cell death pathways, namely, apoptosis, autophagy, and anoikis. Several molecules (e.g., BECN1 and B cell lymphoma 2 [BCL2] family members) are involved in both apoptosis and autophagy, while activation of anoikis leads to cell death similar to apoptosis. These mechanistic similarities suggest that common regulators, including some miRNAs (e.g., miR-21 and miR-192), are involved in different cell death pathways. Because the balance between cell proliferation and cell death is pivotal to the homeostasis of the human body, miRNAs that regulate cell death pathways have drawn much attention from researchers. miR-21 is regulated by several viruses and can affect both apoptosis and anoikis via modulating various targets, such as PDCD4, PTEN, interleukin (IL)-12, Maspin, and Fas-L. miR-34 can be downregulated by viral infection and has different effects on apoptosis, depending on the type of virus and/or host cell. The present review summarizes the existing knowledge on virus-regulated miRNAs involved in the modulation of cell death pathways. Understanding the mechanisms for virus-mediated regulation of cell death pathways could provide valuable information to improve the diagnosis and treatment of many viral diseases.
Upregulation of Antioxidant Capacity and Nucleotide Precursor Availability Suffices for Oncogenic Transformation
2021, Cell Metabolism
The emergence of cancer from diverse normal tissues has long been rationalized to represent a common set of fundamental processes. However, these processes are not fully defined. Here, we show that forced expression of glucose-6-phosphate dehydrogenase (G6PD) affords immortalized mouse and human cells anchorage-independent growth in vitro and tumorigenicity in animals. Mechanistically, G6PD augments the NADPH pool by stimulating NAD⁺ kinase-mediated NADP⁺ biosynthesis in addition to converting NADP⁺ to NADPH, bolstering antioxidant defense. G6PD also increases nucleotide precursor levels through the production of ribose and NADPH, promoting cell proliferation. Supplementation of antioxidants or nucleosides suffices to convert immortalized mouse and human cells into a tumorigenic state, and supplementation of both is required when their overlapping metabolic consequences are minimized. These results suggest that normal cells have a limited capacity for redox balance and nucleotide synthesis, and overcoming this limit might represent a key aspect of oncogenic transformation.
Downregulation of miR-541 induced by heat stress contributes to malignant transformation of human bronchial epithelial cells via HSP27
2020, Environmental Research
Environmental factors are one of the important factors affecting the occurrence of lung cancer. However, few studies have been done on the relationship between hot environment and lung cancer. In the present study, we demonstrated that heat stress leads to anchorage-independent proliferation, mitochondrial apoptosis, and autophagy of Beas-2B cells, which are normal lung bronchial epithelial cells. Heat shock protein 27 (HSP27) promoted heat stress-induced anchorage-independent proliferation and autophagy, but suppressed mitochondrial apoptosis, indicating that HSP27 might act as an oncogene in the malignant transformation of lung epithelial cells. We also showed that HSP27 promoted autophagy of these cells under heat stress via autophagy related 7 (ATG7) and ETS Transcription Factor ELK1 (ELK1), a transcription factor of ATG7, under heat stress. In addition, we showed that HSP27 translation could be repressed by microRNA miR-541, and the biological effects of miR-541 were the opposite to HSP27, suggesting that HSP27 is a downstream target of miR-541. In this study, we characterized a new mechanism whereby HSP27 promotes cell transformation during the onset of lung cancer. Our studies provide new insights into the molecular mechanisms underlying the lung carcinogenic effect of heat exposure. Specifically, heat stress promotes translation of HSP27 by inhibiting miR-541 accumulation, ultimately resulting in activation of autophagy, inhibition of mitochondrial apoptotic pathway and malignant transformation of Human Bronchial Epithelial Cells. This study identifies miR-541 as a potential prognostic biomarker or therapeutic target to improve theory of environmental carcinogenesis.
Genome-wide Screens Implicate Loss of Cullin Ring Ligase 3 in Persistent Proliferation and Genome Instability in TP53-Deficient Cells
2020, Cell Reports
TP53 deficiency is the most common alteration in cancer; however, this alone is typically insufficient to drive tumorigenesis. To identify genes promoting tumorigenesis in combination with TP53 deficiency, we perform genome-wide CRISPR-Cas9 knockout screens coupled with proliferation and transformation assays in isogenic cell lines. Loss of several known tumor suppressors enhances cellular proliferation and transformation. Loss of neddylation pathway genes promotes uncontrolled proliferation exclusively in TP53-deficient cells. Combined loss of CUL3 and TP53 activates an oncogenic transcriptional program governed by the nuclear factor κB (NF-κB), AP-1, and transforming growth factor β (TGF-β) pathways. This program maintains persistent cellular proliferation, induces partial epithelial to mesenchymal transition, and increases DNA damage, genomic instability, and chromosomal rearrangements. Our findings reveal CUL3 loss as a key event stimulating persistent proliferation in TP53-deficient cells. These findings may be clinically relevant, since TP53-CUL3-deficient cells are highly sensitive to ataxia telangiectasia mutated (ATM) inhibition, exposing a vulnerability that could be exploited for cancer treatment.
MiR-96-5p Suppresses Progression of Arsenite-Induced Human Keratinocyte Proliferation and Malignant Transformation by Targeting Denticleless E3 Ubiquitin Protein Ligase Homolog
2023, Toxics

View all citing articles on Scopus

View full text

Cell

ArticleCellular tumorigenicity in nude mice: Correlation with cell growth in semi-solid medium

Abstract

Exp. Cell Res.

Virology

Virology

Virol.

Virology

Science

Int. J. Cancer

Nature

Genetics

Cancer Res.

J. Nat. Cancer Inst.

J. Cell Biol.

Science

Article
Cellular tumorigenicity in nude mice: Correlation with cell growth in semi-solid medium