Inactivation of Autophagy in Keratinocytes Reduces Tumor Growth in Mouse Models of Epithelial Skin Cancer

Caterina Barresi1, Heidemarie Rossiter1, Maria Buchberger1

  • 1Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria.

Cells
|November 26, 2022
PubMed

Insights

Inhibiting autophagy, a cellular process, by deleting the Atg7 gene in skin cells reduced tumor growth in mouse models of skin cancer. This suggests autophagy supports, rather than suppresses, epidermal tumor development.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Dermatology

Background:

  • Autophagy is a fundamental cellular degradation process crucial for maintaining homeostasis.
  • Its role in cancer, specifically whether it suppresses or supports tumor growth, remains a key question in oncology.

Purpose of the Study:

  • To investigate the role of autophagy in epidermal skin tumor development.
  • To determine if inhibiting autophagy affects tumor initiation and progression in the skin.

Main Methods:

  • Inactivated the essential autophagy gene *Atg7* in epidermal keratinocytes of mice.
  • Induced skin tumorigenesis using chemical carcinogens (DMBA/TPA) and a genetic model (K5-SOS EGFR).
  • Compared tumor formation and growth rates between autophagy-deficient (*Atg7* mutant) and autophagy-competent mice.

Main Results:

  • Epithelial *Atg7* deficiency did not prevent tumor formation but significantly reduced the number of tumors per mouse.
  • In the K5-SOS EGFR model, *Atg7* deficient mice showed no tumors of 1 cm diameter, unlike control mice.
  • The deletion of *Atg7* demonstrably reduced the growth of epithelial skin tumors in both models.

Conclusions:

  • Inhibition of autophagy limits the growth of epithelial skin tumors.
  • Autophagy appears to support, rather than suppress, the progression of epidermal tumors.
  • Targeting autophagy could be a potential therapeutic strategy for skin cancer.

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
5.0K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.9K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.7K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.6K