Cell Signaling in Cancer
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Cancer is a complex disease caused by genetic and/or epigenetic changes in one cell or a group of cells. These alterations disrupt "normal" cell function and cause cancerous cells to over proliferate and avoid mechanisms that would typically control their growth, division and migration.1,2 Many of these "disruptions" map to specific cell signaling pathways. This article discusses the relationship between cell signaling and cancer, highlights key signaling pathways involved in cancer and explores how critical mediators of aberrant signaling can be turned into therapeutic targets for cancer.
Contents
The relationship between cell signaling and cancer
- What is cell signaling?
Dysregulated signaling in cancer
Oncogenic mutations, aberrant signaling and tumorigenesis
- Ras proteins
- Wnt/β-catenin signaling
- The NF2 gene
The relationship between cell signaling and cancer
What is cell signaling?
To enable cells to respond and adapt to their environment, they must be able to receive and process information (or "signals") that originate outside of the cell. Cell signaling – also sometimes referred to as signal transduction or transmembrane signaling - controls basic cellular activities via complex responses. Signaling pathways coordinate communication between the cell surface and nucleus, between different cells, and between cells and the extracellular matrix.3“As the foremost system of communication, cell signaling enables individual cells to respond to extracellular signals with physiologically appropriate changes in behavior. Signaling enables normal cells to sense whether their state of attachment to the extracellular matrix and to other cells is appropriate and whether hormones or growth factors call them to proliferate or differentiate, move or stay put, or commit to cell death.” explains Prof. Filippo Giancotti, Department of Cancer Biology, at U.T. MD Anderson Cancer Center, USA.
The Giancotti Laboratory at the MD Anderson Cancer Center investigates the molecular basis of tumor initiation and progression to metastasis with an emphasis on the role of cell adhesion and signaling. The current major focus of the lab is on identifying the mechanisms that enable the survival during dormancy and eventually the reactivation of metastatic stem cells.
Dysregulated signaling in cancer
Aberrant signaling of just one pathway can have huge implications on wider signaling networks that consequently promote cancer progression and metastasis.1 Disrupted cell signaling in cancer is responsible for numerous specific characteristics of tumor cells that distinguish them from "normal" cells – these features are known as "The Hallmarks of Cancer" (Figure 1).2,4
Figure 1: The 10 hallmarks of cancer, as defined by Douglas Hanahan and Robert A. Weinberg, 2011.
Giancotti continues: “Whereas many oncogenes are activated versions of signaling proteins, many tumor suppressors normally repress signaling. Thus, oncogenic mutations disrupt the signaling circuits that control cell adhesion and signaling, enabling cells that carry them to proliferate and invade in an uncontrolled fashion.”
Here we highlight three examples that can be used to exemplify signaling pathways that are aberrantly activated in cancer:
Giancotti highlights two examples of Ras-affected pathways: “The Ras protein is a GTPase that controls activation of the Raf-MEK-extracellular signal-regulated kinase (ERK) and PI-3K-AKT signaling pathways and, through them, regulates cell survival, cell proliferation and migration/invasion in response to matrix adhesion and growth factor stimulation.”
Mammalian cells express three distinct but closely related Ras proteins (K-Ras, H-Ras and N-Ras), which can become mutationally activated which in turn promotes oncogenesis. The mutation frequency of different Ras in human cancers varies, and of the three, K-Ras is the most frequently mutated isoform.6
“Ras proteins are mutated in such a way that enables constitutive signaling and therefore uncontrolled proliferation and migration/invasion in many cancer types.”
Giancotti continues: “Whereas many oncogenes are activated versions of signaling proteins, many tumor suppressors normally repress signaling. Thus, oncogenic mutations disrupt the signaling circuits that control cell adhesion and signaling, enabling cells that carry them to proliferate and invade in an uncontrolled fashion.”
Oncogenic mutations, aberrant signaling and tumorigenesis
Here we highlight three examples that can be used to exemplify signaling pathways that are aberrantly activated in cancer:Ras proteins
Ras proteins act as molecular switches that control the activation and regulation of pathways, that are responsible for numerous cell behaviors.5Giancotti highlights two examples of Ras-affected pathways: “The Ras protein is a GTPase that controls activation of the Raf-MEK-extracellular signal-regulated kinase (ERK) and PI-3K-AKT signaling pathways and, through them, regulates cell survival, cell proliferation and migration/invasion in response to matrix adhesion and growth factor stimulation.”
Mammalian cells express three distinct but closely related Ras proteins (K-Ras, H-Ras and N-Ras), which can become mutationally activated which in turn promotes oncogenesis. The mutation frequency of different Ras in human cancers varies, and of the three, K-Ras is the most frequently mutated isoform.6
“Ras proteins are mutated in such a way that enables constitutive signaling and therefore uncontrolled proliferation and migration/invasion in many cancer types.”
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The Ras-Raf-MEK-ERK signaling cascade can be activated by several different stimuli (e.g., receptor tyrosine kinase and G protein-coupled receptors). Mutations in Ras as well as other upstream receptor genes can result in abnormal Ras-Raf-MEK-ERK signal activation. This specific pathway plays a key role in the development of hepatocellular carcinoma (HCC) and breast cancers.6
Ras, Raf, MEK, ERK, as well as other associated molecules have gained much attention as potential therapeutic targets for cancer. Some examples of inhibitors are listed in Table 1.
Ras, Raf, MEK, ERK, as well as other associated molecules have gained much attention as potential therapeutic targets for cancer. Some examples of inhibitors are listed in Table 1.
Table 1: Examples of Ras-Raf-MEK-ERK signaling inhibitors
| MEK inhibitors | RAF inhibitor | RAS inhibitor |
| Sorafenib (BAY 43-9006, Nexavar) | pan-Ras inhibitor 3144 |
Wnt/β-catenin signaling
Dysregulated Wnt signaling is linked to numerous cancers including; leukemia, melanoma, breast and gastrointestinal cancers.7 In fact, a 2012 report by The Cancer Genome Atlas (TCGA) consortium estimated that >90% of sporadic colorectal cancers contained at least one alteration in a Wnt pathway regulator.“Mutations that prevent degradation of β-catenin, such as certain mutations in β-catenin itself or in the destruction complex component APC, hijack regenerative signaling and contribute to the development of colorectal cancer and other malignancies.” says Giancotti.
Adenomatous polyposis coli (APC) is a negative regulator of the canonical Wnt signaling (β-catenin dependent) pathway and is capable of binding to numerous proteins including β-catenin. A condition known as familial adenomatous polyposis, characterized by cancer of the colon and rectum, results from mutations in the APC gene.7,8
Vivian Li, Group Leader at the Francis Crick Institute expands on the relationship between APC, Wnt signaling and colon cancers: “Wnt signaling is a genetic pathway that functions to promote cell growth. In normal cells this Wnt signaling pathway is carefully controlled by a gene called APC, which functions to prevent excessive cell growth and tumor formation. However, the majority of colon cancers actually have mutations in the APC gene which eventually causes hyperactivation of the pathway leading to cancer.”
Li’s team’s research focuses on elucidating how normal and aberrant Wnt signaling and how this affects the programming of stem cells. Using three-dimensional cell models, known as organoids, and gene-editing techniques they can alter the levels of Wnt, and other signaling molecules to determine the effect on bowel stem cells.
Numerous Wnt-signaling pathway inhibitors are being explored for a range of different cancers including colorectal, melanoma and breast.5
Table 2: Examples of Wnt-signaling pathway inhibitors7
| Porcupine inhibitors | Antibodies against Wnt family proteins | Wnt co-activator antagonists |
| PRI-724 |
Li touches on the importance of identifying the "right" target: “The Wnt signaling pathway is important not only for cancer cells, but also for many other healthy organs. For example – in the gut the Wnt signaling pathway is required to maintain stem cell populations for tissue repair. Identifying a tumor specific target is important for developing safe and effective drugs that target this pathway.”
“Merlin activates the Hippo tumor suppressor pathway and represses the TOR pathway. When mutated, it contributes to the development of familial Schwann cell tumors and, in individuals exposed to asbestos, to malignant lung mesotheliomas.” says Giancotti.
Several other types of cancer are linked to mutated NF2 and Merlin inactivation, including Glioblastoma multiforme, breast, colorectal, skin, hepatic and prostate cancer.10,11
According to Giancotti the most powerful methods for dissecting signaling pathways include: “genetic analysis in Drosophila and other model organisms and biochemical analysis in xenopus oocytes and cultured mammalian cells”. He explains that they are most powerful when used in conjunction with each other.
“More recently, chemical biology and genetic screening coupled to high-resolution imaging have added to the armamentarium of cell signaling research.” He adds.
When it comes to identifying critical mediators of aberrant signaling or perhaps even identifying previously unknown signaling pathways that could be therapeutically targeted, Giancotti explains that high-throughput screening in vitro or in model organisms is key.
“In such assays, sh-RNA or g-RNA libraries are used to identify genes that repress activation of a reporter or a phenotype, whereas ORFeome libraries are used to identify genes that activate the same. Coupling such screens with a small molecule screen may yield novel compounds that target the pathway under examination.”
One of the most challenging aspects of cancer drug discovery is at the stage of target validation – whereby you must demonstrate the functional role of the identified target in the disease phenotype.12
“Even the most sophisticated genetically engineered mouse models (GEMMs) or comprehensive collections of patient-derived xenografts (PDXs) do not fully recapitulate the heterogeneity of human tumors and thus their dependency on signaling pathways X, Y or Z. Moreover, tumor cells are extremely adaptable and can resist therapy by acquiring additional mutations or by changing their fate so that they no longer depend on the oncogenic pathway originally targeted.”
The NF2 gene
The Neurofibromatosis Type 2 (NF2) gene acts as a tumor suppressor and encodes a cytoskeletal protein called moesin-ezrin-radixin-like protein or "Merlin" (sometimes also referred to as schwannomin). Merlin helps regulate several signaling pathways responsible for controlling cell shape, growth, adhesion – it stops cells from dividing in an uncontrolled way by sensing cell-to-cell contact and restricting proliferation.9,10“Merlin activates the Hippo tumor suppressor pathway and represses the TOR pathway. When mutated, it contributes to the development of familial Schwann cell tumors and, in individuals exposed to asbestos, to malignant lung mesotheliomas.” says Giancotti.
Several other types of cancer are linked to mutated NF2 and Merlin inactivation, including Glioblastoma multiforme, breast, colorectal, skin, hepatic and prostate cancer.10,11
Exploring the complex signaling circuits involved in cancer
According to Giancotti the most powerful methods for dissecting signaling pathways include: “genetic analysis in Drosophila and other model organisms and biochemical analysis in xenopus oocytes and cultured mammalian cells”. He explains that they are most powerful when used in conjunction with each other.“More recently, chemical biology and genetic screening coupled to high-resolution imaging have added to the armamentarium of cell signaling research.” He adds.
When it comes to identifying critical mediators of aberrant signaling or perhaps even identifying previously unknown signaling pathways that could be therapeutically targeted, Giancotti explains that high-throughput screening in vitro or in model organisms is key.
“In such assays, sh-RNA or g-RNA libraries are used to identify genes that repress activation of a reporter or a phenotype, whereas ORFeome libraries are used to identify genes that activate the same. Coupling such screens with a small molecule screen may yield novel compounds that target the pathway under examination.”
One of the most challenging aspects of cancer drug discovery is at the stage of target validation – whereby you must demonstrate the functional role of the identified target in the disease phenotype.12
“Even the most sophisticated genetically engineered mouse models (GEMMs) or comprehensive collections of patient-derived xenografts (PDXs) do not fully recapitulate the heterogeneity of human tumors and thus their dependency on signaling pathways X, Y or Z. Moreover, tumor cells are extremely adaptable and can resist therapy by acquiring additional mutations or by changing their fate so that they no longer depend on the oncogenic pathway originally targeted.”
Despite the difficulty of finding a truly efficacious drug – there are numerous success stories. Giancotti highlights some examples of therapeutics used for the treatment of cancer that target signaling: “Imatinib (Gleevec) was the first oncogene-targeted therapy developed for cancer treatment. It is a catalytic inhibitor of the ABL tyrosine kinase, which controls proliferative signaling in myeloid cells. ABL is activated by translocation in chronic myelogenous leukemia (CML). Imatinib is extremely efficacious in CML.”
Giancotti says that the majority of patients treated with imatinib enter into a state of very durable remission and their life expectancy is comparable to that of similarly aged healthy individuals.
B-RAF inhibitors present as another example and are extremely efficacious in B-RAF mutated melanoma. “… especially if used in conjunction with immunotherapy” explains Giancotti. “The idea here is that the cell killing consequent to B-RAF kinase inhibition generates neoantigens recognized by the patient’s immune system.”
Other examples include drugs targeting the estrogen receptor (ER) in breast cancer and androgen receptor (AR) in prostate cancer, as well as monoclonal antibodies targeting the ERBB2 tyrosine kinase, such as trastuzumab (Herceptin) which has demonstrated efficacy in particular breast cancers (those that involve amplifications of ERBB2 which drives uncontrolled mitogenic signaling).
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2. Mason LE. Cancer cells vs normal cells. Technology Networks. Accessed December 12, 2018. https://www.technologynetworks.com/cancer-research/articles/cancer-cells-vs-normal-cells-307366
3. Bradshaw RA, E. A. Dennis EA. (2009) Handbook of Cell Signaling. (2nd ed.) Academic Press. doi: 10.1016/B978-0-12-374145-5.X0001-0
4. Giancotti F. Deregulation of cell signaling in cancer. FEBS Letters, 2014; 588(16), 2558-2570. doi: 10.1016/j.febslet.2014.02.005
5. Prior I, Lewis P, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72(10),2457-2467. doi: 10.1158/0008-5472.can-11-2612
6. Li L, Zhao G, Shi Z, Qi L, Zhou L, Fu Z. The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncol Lett. 2016;12(5),3045-3050. doi: 10.3892/ol.2016.5110
7. Mason LE. The role of Wnt signaling in cancer. Accessed December 12, 2018. https://www.technologynetworks.com/cancer-research/articles/the-role-of-wnt-signaling-in-cancer-305127
8. Aoki K, Taketo M. Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene. J. Cell Sci. 2007;120(19),3327-3335. doi: 10.1242/jcs.03485
9. Genetics home reference, your guide to understanding genetic conditions. NF2 gene. Accessed December 13, 2018. https://ghr.nlm.nih.gov/gene/NF2
10. Cooper J, Giancotti F. Molecular insights into NF2/Merlin tumor suppressor function. FEBS Letters, 2014;588(16),2743-2752. doi: 10.1016/j.febslet.2014.04.001
11. Petrilli A, Fernández-Valle C. (2015). Role of Merlin/NF2 inactivation in tumor biology. Oncogene. 2015;35(5),537-548. doi: 10.1038/onc.2015.125
12. Lansdowne LE. Target identification & validation in drug discovery. Technology Networks. Accessed December 13, 2018. https://www.technologynetworks.com/drug-discovery/articles/target-identification-validation-in-drug-discovery-312290
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