Evade Growth Suppressors (insensitivity to anti-growth signals)
Evade Growth Suppressors is one of the key Hallmarks of Cancer, as the evasion of anti-growth signaling is an important characteristic of cancer cells.
Cell division is controlled through the cell cycle in a series of tightly regulated events involving intricate pathways of signalling and checkpoints that prevent the perpetuation of dividing cells containing damaged DNA. Essentially, a cell has 3 options:
- continue to grow by dividing and remaining within the cell cycle,
- take a temporary break to become quiescent by entering G0, or
- exit the cell cycle permanently to the post-mitotic state.
Two interdependent regulatory proteins, Cyclin and Cyclin-Dependent Kinases (CDKs), control the checkpoints. The cyclin/CDK complex allows the cell to commit to the next stage of the cell cycle.
To ensure cell division doesn’t continue unchecked, a cell responds to anti-growth signals. These anti-growth signals are proteins that inhibit rather than promote cell growth either through G0 (quiescence, temporary break) and post-mitotic state (permanently exit the cell cycle).
Cancer cells display uncontrolled cell division through a failure to respond to anti-growth signals by evading growth suppressors. The Retinoblastoma (Rb) tumor suppressor gene encodes the protein that regulates cell proliferation by controlling progression through the G1 cell cycle checkpoint. Retinoblastoma has three unique binding domains and interacts with regulatory proteins including transcription factors and the c-Abl tyrosine kinase. Retinoblastoma is dysfunctional in several major cancers and loss-of-function mutants of Rb have been found in a host of cancers.
(i) Retinoblastoma controls anti-growth signalling
Retinoblastoma manages antigrowth signals when DNA damage is detected at a specific point in the cell cycle. However, Rb can become inactivated when phosphorylated by active CDKs acting on external cell division signals. The result is E2F transcription factors allow the cell cycle to proceed.
Retinoblastoma activation is influenced by antigrowth signals from the microenvironment of the cell. Cancer cells succeed in bypassing these antigrowth signals so that Rb pathway free E2F factors to promote cell division leading to uncontrolled tumor growth.
ATCC® have identified and validated the Rb gene and protein sequence in several cell lines across various cancers. Tumor cell lines become more powerful tools for cancer research and drug discovery when the genetic abnormalities that drive their phenotype are known. ATCC now offers our reliable, authenticated tumor cell lines annotated with gene mutation information from the Sanger Institute COSMIC database. This guide organizes ATCC tumor cell lines according to the gene of interest, and provides information for each line about the specific mutation, predicted protein sequence, zygosity, and tumor histology. ATCC has collected this information together so that you can quickly select the cell lines that best suit your research needs.
Need more information on the Rb status in ATCC® Tumor Cell Lines?
> Download the Cell Lines by Gene Mutation Brochure
(ii) TGF-β is the most well-known antigrowth signal
TGF-beta has several mechanisms that prevent Rb phosphorylation suggesting that TGF-beta blocks the progress of the cell cycle. These mechanisms include:
- many cancers disrupt the TGF-beta pathway,
- some cancers produce less TGF-Beta receptors therefore not responding to TGF-beta
- some cancers produce mutated TGF-beta receptors, thus avoiding a response to TGF-beta
- some cancers get rid of downstream proteins that respond to TGF-beta
- in late-stage tumors, instead of TGF-beta acting as an antigrowth signal, it activated EMT giving cancer cells stem-cell-like ability.
- Rb gene mutates so that the Rb protein is lost
- Some oncoproteins can block Rb function
Cancer cells displaying defects in Rb pathway lack a cell cycle ‘gatekeeper’ leading to persistent cell division.
Explore the TGF-β family from R&D Systems.
> Download the TGF-β Signalling pathways Poster.
Flanders et al (2016) successfully used R&D Systems TGF-β Luminex Performance Assay kit to simultaneously detect and quantitate TGF-β isoforms in multiple samples and tissue types.
Using this multiplex assay this study reported that the Quantitation of TGF-β proteins in mouse tissues shows reciprocal changes in TGF-β1 and TGF-β3 in normal vs neoplastic mammary epithelium.
Figure shows that TGF-β1, 2, and 3 were quantitated by multiplex assay from acid-ethanol extracts of tissues from 9 wk old female BALB/c mice, or from 15 d gestation BALB/c embryos (Flanders et al 2016).
TGF- β Premixed Magnetic Luminex Performance Assay enable simultaneous detection and quantitation of multiple target analytes in qualified complex sample types. Luminex bead-based multiplex assays are designed to provide accurate, reproducible results for every target analyte.
The Benefits of Multiplexing with R&D Systems Luminex Assays
Examining multiple factors simultaneously in a single sample volume, also known as multiplexing, can provide numerous benefits to the user.
- Maximizes Limited Sample: Multiplexing allows the user to maximize data collection from a small sample volume.
- Minimizes Experimental Variability: Examining multiple factors at one time removes a layer of variability from data, as the sample is processed only once and multiple data points are derived from a single manipulation.
- Optimizes Productivity: Allowing users to collect multiple data points while minimizing sample preparation and processing saves time and generates high volumes of data.