Carcinoma Signaling

Carcinoma Signaling

Disruption of intracellular signaling is fundamental to a variety of diseases, including cancer. There are numerous signaling pathways which control cell proliferation and cell death in normal cells. The conversion of normal cells to cancer cells has been shown to be associated with errors in these signaling pathways. Signaling pathways in cells refer to a complex network of different proteins which develop an intricate communication system in the cells. There are receptors on the cell membrane which receive external stimuli and convey the message through this communication system to the nucleus where synthesis of necessary proteins is regulated accordingly. This ultimately triggers a specific cellular response.

There are various signaling pathways that lead to uncontrolled cell divisions. Major ones are the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades. These signaling cascades can work independently or cross-talk with other pathways. JAK/STAT, Notch, Wnt and TGF-β pathways are some of the other pathways that play an important role in cancer. We will discuss the role of these pathways in cancer in brief.

Phosphatidyl inositol-3-kinase (PI3K)/AKT pathway

The pathway: The phosphatidylinositol-3-kinase (PI3K)/ signaling pathway plays a major role in regulating cell growth and survival in a wide variety of human cancers. This pathway is often targeted by gene mutations, amplifications and rearrangement. Activation of this pathway disrupts the regulation over cell proliferation and death which then leads to cancer. Thus, a drug that could affect the PI3K signaling pathway would be a good target for the development of novel anti-cancer drugs.

The PI3K–AKT signaling pathway is inappropriately activated in many cancers. There are multiple different molecules in this pathway. Currently, the involvement of AKT in cancer is one of the most interesting areas of study. AKT in turn activates mTOR, which broadly mediates cell growth and proliferation. Two well-known mechanisms of PI3K/AKT activation involved in most human cancers are activation by receptor tyrosine kinases (RTKs) and specific somatic mutations.

Abnormalities of the pathway in cancer: The PI3K/AKT pathway is constitutively activated in numerous human cancers. Activation of this pathway can promote cell survival and proliferation.

Examples of potential as drug target: There are several molecules that target the PI3K/AKT pathway in clinical development for the treatment of cancer. All these are novel, oral anticancer agents.

Epidermal growth factor receptor (EGFR) and HER2/ErbB-2

The pathway: One of the most studied growth factor receptor systems is the HER (also defined erbB) family. This family consists of four distinct, but structurally similar, transmembrane tyrosine kinase (TK) receptors, named HER1/erbB-1 (better known as endothelial growth factor receptor [EGFR]), HER2/erbB-2, HER3/erbB-3 and HER4/erbB-4.

Several molecules such as endothelial growth factor (EGF), transforming growth factor-a (TGF-a), and heparin-binding EGF bind to EGFR or HER 1. These are called ligands. Binding of these ligands to the receptors activates the signaling cascade. Downstream to this cascade are two very important signaling pathways: the Ras-MAPK pathway and PI3K pathway. This signaling pathway mainly regulates many kinds of growth in cells.

Abnormalities of the pathway in cancer: The HER receptors and their ligands are frequently overexpressed in many tumor types, including those of epithelial and mesenchymal lineage, and have been implicated in cancer pathogenesis. Further, they are also associated with poor prognosis. In such cases where HER 2 is overexpressed, the treatment has to be modified. As an example, HER-2 overexpression in breast cancer is associated with an adverse prognosis.

Examples of potential as drug target: A large body of preclinical studies and clinical trials conducted so far suggests that targeting the EGFR and HER-2 may provide a significant contribution to cancer therapy. Monoclonal antibodies against these targets or inhibitors of EGFR-TK autophosphorylation and downstream signaling can be potential drugs. An example is Trastuzumab (monoclonal antibodies against HER2), which may be a drug for the future.

Protein kinase C (PKC) family

The pathway: The PKC family consists of at least 12 closely related isozymes that have distinct and, in some cases, opposing roles in cell growth and differentiation. Activation of cell surface receptors, such as EGFR and platelet-derived growth factor receptor (PDGF-R), triggers reactions which ultimately activate PKC. PKC isozymes play an important role in the control of cell proliferation, migration, adhesion, and malignant transformation. In addition, PKC is also related to invasion and cancer cell metastasis.

Abnormalities of the pathway in cancer: Alterations in expression of PKC isozymes is associated with various types of cancers. Over-expression of PKCα has been associated with cancer in breast, lung and stomach.

Examples of potential as drug target: Small molecules that can inhibit the PKC isozymes have been designed and are in clinical trials. Examples: Gleevec (imatinib) and Iressa (gefitinib).

SOS-Ras-Raf-MAPK signaling cascade

The pathway: The RAS-Mitogen Activated Protein Kinase (MAPK) pathway is activated by cytokines and growth factors through Receptor Tyrosine Kinases (RTK) to promote cell adhesion, proliferation, migration and survival.

This signaling pathway begins with Son Of Sevenless (SOS) which activates RAS, a small membrane-bound GTPase. Upon receptor signaling, SOS shuttles to the cell membrane to begin a series of reactions which ultimately activate mitogen-activated protein kinases (MAPKs). Other compounds in this sequence of events include ERKs, JNK, and p38. Generally, the ERK pathway is activated by growth factor-stimulated cell surface receptors, whereas the JNK, p38 and ERK5 pathways are activated by stress and growth factors.

Abnormalities of the pathway in cancer: The SOS-Ras-Raf-MAPK signaling cascade is deregulated in a variety of human tumors. Most of these mutations occur in RAS and RAF. These mutations result in constitutive activation of the signaling pathway. RAS mutations are found in colon and pancreatic cancers. RAF mutations, in turn, are mostly detected in melanomas.

Examples of potential as drug target: This pathway is a strong target for therapeutic intervention.

JAK/STAT pathway

The pathway: The JAK-STAT system consists of three main components: a receptor, JAK and STAT. The JAK/STAT pathway is intimately linked to growth factor signaling, apoptosis (cell death) and the cellular immune response.

Abnormalities of the pathway in cancer: Deregulated JAK/STAT signaling can contribute directly and indirectly to tumorigenesis. Components of this pathway have been associated with variety of cancers, for example, HER2/neu- in mammary and stomach carcinomas, Epidermal Growth Factor-Receptor (EGF-R) in breast, brain and stomach tumors. Furthermore, STAT3 is constitutively activated in several major human carcinomas. For example: STAT3 is persistently active in head and neck cancers, lung cancers and breast cancers.

Examples of potential as drug target: Ruxolitinib (INCB18424, Incyte Corporation), an inhibitor that targets both JAK1 and JAK2 is a potential anti-cancer.

Notch pathway

The Notch signaling pathway consists of a membrane bound protein, which upon ligand binding undergoes proteolytic cleavage and releases a transcription factor that goes to the nucleus. The ligands include Delta (or Delta-like) and Jagged/Serrate families of membrane-bound ligands. Their binding to the Notch receptors (1-4), results in two proteolytic cleavage events in the Notch receptor. The notch signaling pathway regulates cell fates, cell proliferation and cell death during embryonic and adult life.

Abnormalities of the pathway in cancer: The dysregulation or loss of Notch signaling is associated with a wide range of and cancer. Aberrant Notch signaling pathways have been associated with T-cell acute lymphoblastic leukemia / lymphoma (T-ALL), human breast tumors, melanoma progression, medullablastoma and ovarian cancers.

Examples of potential as drug target: Gamma secretase inhibitors are already being tried as Notch inhibitors for treatment of colon carcinoma.

Wnt pathway

The pathway: The Wnt pathway has three branches. Among these three, the canonical branch of the pathway has been implicated in tumorigenesis.

Abnormalities of the pathway in cancer: Wnt signaling activating mutations in APC or β-catenin are frequently found in small intestinal adenocarcinomas and gastric polyps. Aberrant Wnt-signaling is also found in chronic and acute myeloid leukemia.

Potential as drug target: Inhibitors of the Wnt pathway are novel drugs against colon cancer.

TGF-β pathway

The TGF-β superfamily comprises of two subfamilies. One of them is consisted of TGF-β, activin, Nodal, myostatin, and inhibin. The other one includes BMPs, anti-mullerian hormone (AMH, or MIS), as well as many growth and differentiation factors (GDFs) which have intense effects on cellular proliferation, differentiation, and growth.

The Transforming Growth Factor-β (TGF-β) is a secreted protein that has at least 5 isomers. Once activated, they bind to specific receptors and phosphorylated them. Phosphorylation of SMADs leads to their activation and a higher-order complex formation. Finally, they enter the nucleus and control the transcription of a wide array of genes.

Abnormalities of the pathway in cancer: Mutations or down-regulation of TGF-β receptors, inactivation of SMAD4 and other similar molecules can be found in a variety of cancers. Examples include SMAD4 inactivation in human pancreatic ductal adenocarcinomas, BMP2 overexpression in lung carcinomas. TGF-β signaling can also stimulate metastasis.

Potential as drug target: Lerdelimumab (CAT-152, Trabio™), Metelimumab (CAT-192) and many other inhibitors are in clinical trials.

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  9. This article was originally published on September 3, 2012 and last revision and update was 9/4/2015.