Roles on RTKs and HER in Cervical Cancer

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27th Sep 2017 Health Reference this

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1.2 Cervical Cancer

Cervical cancer is the fourth cancer most common in women, and the seventh overall, with an estimated 528 000 new cases and 266 000 deaths in 2012

Usually, cervical cancer arises from a ring of mucosa called the cervical transformation zone A large majority of cervical cancers are squamous cell carcinomas that develop in squamous cells that cover the surface of the exocervix. Cervical adenocarcinomas seems to become more common in the last 30 years and they develop from the mucus-producing gland cells of the endocervix. Less commonly, cervical tumors have features of both squamous cells carcinomas and adenocarcinomas so these are called adenosquamous carcinomas

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The infection with human papilloma virus (HPV) is considered the necessary cause of cervical cancer, as more than 96% of cervical cancers are positive for high-risk HPV viruses, especially type 16, the most predominant type identified in precancerous lesions and in cervical cancer. Other high-risk HPV types, such as 18, 31, 33, 35 are, even less frequently, involved in HPV related carcinogenesis from high-grade cervical intraepithelial neoplasia (CIN) to invasive carcinoma. In vitro studies with cervical cell lines have indicated that the oncogenic properties of high-risk HPV types can be attributed mainly to two HPV proteins, the HPV E6 and E7 proteins Oncoprotein E6 causes degradation of P53, leading to apoptosis invasion and oncoprotein E7 causes inactivation of retinoblastoma

Throughout the world, human papillomavirus (HPV)-associated disease is an immense public health burden. At least 50% of men and women will acquire genital HPV infection during their lifetime. HPV infection is frequently acquired in adolescents and young adults within months after first sexual intercourse but not all of women who contract the virus developed cancer

1.3 Receptor Tyrosine Kinases

There is a marvelous coordinated orchestrated balanced sequence of events that controls normal cell function, cell division and programmed cell death. There is even a more complex physiologic regulation that allows repair and restoration of any dysfunction that may occur. When these functions are disturbed it could exist dedifferentiation and uncontrolled proliferation that characterizes carcinogenesis

Cell membrane receptors receive and transmit signals from the environment and some of these receptors also doubles as enzymes. When they act like enzymes the binding of a signaling molecule to them activates the inherent enzymatic activity and one of the various examples of receptors with this capability are receptor tyrosine kinases (RTK)

Since the discovery of the first RTK more than a quarter of a century ago, many members of this family of cell-surface receptors have emerged as key regulators of critical cellular processes, such as proliferation and differentiation, cell survival and metabolism, and cell migration (Figure 1)

Humans have 58 known RTKs, which fall into 20 subfamilies. All RTKs have a similar molecular architecture, with ligand binding domains in the extracellular region, a single transmembrane helix, and a cytoplasmic region that contains the protein tyrosine kinase domain plus additional carboxyl (C-) terminal and juxtamembrane regulatory regions

The ligands for RTK’s are soluble or membrane-bound protein hormones including, for example, nerve growth factor (NGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF). Growth factors and hormones are thus two especially important categories of signaling molecules that bind to RTKs

When the ligand binds to RTK they cause the formation of cross-linked dimmers between the receptors. Cross-linking activates the tyrosine kinase activity through phosphorylation, more specifically each RTK in the dimmer phosphorylates multiple tyrosines on the other RTK being this process called cross-phosphorilation

Once cross-phosphorylated, the cytoplasmic tails of RTKs serve as docking platforms for various intracellular proteins involved in signal transduction. These proteins have a particular domain, called SH2, which binds to phosphorylated tyrosines in the cytoplasmic RTK receptor tails. More than one SH2-containing protein can bind at the same time to an activated RTK, allowing simultaneous activation of multiple intracellular signaling pathways like MAPK/Erk and Akt pathway (Figure 1)

The Erk pathway is activated by a wide range of receptors involved in growth and differentiation including RKT’s. Briefly, a set of adaptors linking the receptor to a guanine exchange factor transducing the signal to small GTP-binding proteins which in turn activate the core unit of cascade. An activated Erk dimer can regulate the cytosol targets and also translocate to the nucleus where it phosphorylates a variety of transcription factors regulating gene expression

The serine/threonine Akt kinase is a proto-oncogene and has a critical regulatory function in cancer progression and insulin metabolism. This pathway is activated by RTK’s and other stimuli that induce PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle

Aberrant activation of RTKs in human cancers is mediated by three principal mechanisms: autocrine activation, chromosomal translocations, gene amplification and RTK overexpression

Several drugs have been developed and approved by the US Food and Drug Administration for treating cancers and other diseases caused by activated RTKs and these drugs fall into two categories, small molecule inhibitors that target the ATP-binding site of the intracellular TKD and monoclonal antibodies that both interfere with RTK activation and target RTK-expressing cells for destruction by the immune system

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1.4 The HER Family

The HER family (or ErBb) of receptors comprises the family I of RTKs that includes EGFR, HER2, HER3 and HER4. Each of the receptors is a type I transmembrane protein consisting of a heavily glycosylated ectodomain that contains a ligand binding site, a single transmembrane domain, an intracellular protein-tyrosine kinase catalytic domain (TKD) and a tyrosine-containing cytoplasmic tail One exception is HER3 because this receptor lacks intrinsic tyrosine activity, so the receptor can only initiate signal transduction when dimerized with another HER family member.

http://ebm.sagepub.com/content/236/4/375/F1.large.jpgFigure 1. Schematic representation of a representative RTK, EGFR. After ligand binding occurs phosphorilation of the receptor that leads to activation of signaling pathways (Lee et al. 2011).

In general, growth factor binding to regions I and III in the ectodomain induces a conformational change to convert the receptor ectodomain from a tethered, inactive conformation to an extended, active conformation

The four EGF receptors recognize thirteen different but structurally related growth factors (Figure 2). EGFR is regulated by at least seven different activating ligands in humans: EGF itself, transforming growth factor a (TGF-a), betacellulin (BTC), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (ARG), epiregulin (EPR), and epigen (EGN). Each contains an EGF-like domain that is responsible for receptor binding and activation, with a characteristic pattern of six spatially conserved cysteines. For HER2, no soluble ligand has been identified. This orphan receptor is generally assumed only to be regulated by heterodimerization with other HER family receptors. HER3 and HER4 are regulated by neuregulins in a wide variety of different isoforms that all contain an EGF-like domain. Three of the EGFR ligands previously mentioned (BTC, EPR, and HB-EGF) also bind and activate HER4 and are termed “bispecific” ligands

ErbB

Figure 2. Schematic representation of HER family members with possible ligands and possible pairs of dimmers (Zhang et al. 2007)

Importantly, EGFR and his relatives are known oncogenic drivers in cancer such as lung cancer, breast cancer and glioblastoma and inhibitors of these receptors have been among the most successful examples of targeted cancer therapies to date, including antibody therapeutics (e.g., trastuzumab and cetuximab) and small-molecule tyrosine kinase inhibitors (e.g., erlotinib, gefitinib, lapatinib)

1.5 The HER Family in cervical cancer

Concerning cervical cancer, the expression of EGFR appears to have a direct association with human papillomavirus (HPV) infection, as evidenced by its increasing expression as the grade of intraepithelial neoplasia increases Some studies indicated that EGFR expression is associated with poor response to chemoradiation while other studies have not found such an association with poor prognosis

HER2 is also rarely expressed in the normal surface epithelia of the lower genital tract, with higher HER2 expression in the basal layer compared with the surface layer The degree and frequency of HER2 overexpression in cervical lesions has been directly correlated with the grade of dysplasia or stage of cancer

In squamous cells carcinomas HER3 is known to be expressed in the large majority of those and is correlated with poor prognosis

The role of HER4 in cancer is not well understood however Campiglio et al. suggests that HER3/HER4 heterodimers may be responsible for prolonged activation of mitogen-associated protein kinase (MAPK) that causes cellular proliferation. On the other hand, Feng et al. associates HER4 with cell growth inhibition

1.2 Cervical Cancer

Cervical cancer is the fourth cancer most common in women, and the seventh overall, with an estimated 528 000 new cases and 266 000 deaths in 2012

Usually, cervical cancer arises from a ring of mucosa called the cervical transformation zone A large majority of cervical cancers are squamous cell carcinomas that develop in squamous cells that cover the surface of the exocervix. Cervical adenocarcinomas seems to become more common in the last 30 years and they develop from the mucus-producing gland cells of the endocervix. Less commonly, cervical tumors have features of both squamous cells carcinomas and adenocarcinomas so these are called adenosquamous carcinomas

The infection with human papilloma virus (HPV) is considered the necessary cause of cervical cancer, as more than 96% of cervical cancers are positive for high-risk HPV viruses, especially type 16, the most predominant type identified in precancerous lesions and in cervical cancer. Other high-risk HPV types, such as 18, 31, 33, 35 are, even less frequently, involved in HPV related carcinogenesis from high-grade cervical intraepithelial neoplasia (CIN) to invasive carcinoma. In vitro studies with cervical cell lines have indicated that the oncogenic properties of high-risk HPV types can be attributed mainly to two HPV proteins, the HPV E6 and E7 proteins Oncoprotein E6 causes degradation of P53, leading to apoptosis invasion and oncoprotein E7 causes inactivation of retinoblastoma

Throughout the world, human papillomavirus (HPV)-associated disease is an immense public health burden. At least 50% of men and women will acquire genital HPV infection during their lifetime. HPV infection is frequently acquired in adolescents and young adults within months after first sexual intercourse but not all of women who contract the virus developed cancer

1.3 Receptor Tyrosine Kinases

There is a marvelous coordinated orchestrated balanced sequence of events that controls normal cell function, cell division and programmed cell death. There is even a more complex physiologic regulation that allows repair and restoration of any dysfunction that may occur. When these functions are disturbed it could exist dedifferentiation and uncontrolled proliferation that characterizes carcinogenesis

Cell membrane receptors receive and transmit signals from the environment and some of these receptors also doubles as enzymes. When they act like enzymes the binding of a signaling molecule to them activates the inherent enzymatic activity and one of the various examples of receptors with this capability are receptor tyrosine kinases (RTK)

Since the discovery of the first RTK more than a quarter of a century ago, many members of this family of cell-surface receptors have emerged as key regulators of critical cellular processes, such as proliferation and differentiation, cell survival and metabolism, and cell migration (Figure 1)

Humans have 58 known RTKs, which fall into 20 subfamilies. All RTKs have a similar molecular architecture, with ligand binding domains in the extracellular region, a single transmembrane helix, and a cytoplasmic region that contains the protein tyrosine kinase domain plus additional carboxyl (C-) terminal and juxtamembrane regulatory regions

The ligands for RTK’s are soluble or membrane-bound protein hormones including, for example, nerve growth factor (NGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF). Growth factors and hormones are thus two especially important categories of signaling molecules that bind to RTKs

When the ligand binds to RTK they cause the formation of cross-linked dimmers between the receptors. Cross-linking activates the tyrosine kinase activity through phosphorylation, more specifically each RTK in the dimmer phosphorylates multiple tyrosines on the other RTK being this process called cross-phosphorilation

Once cross-phosphorylated, the cytoplasmic tails of RTKs serve as docking platforms for various intracellular proteins involved in signal transduction. These proteins have a particular domain, called SH2, which binds to phosphorylated tyrosines in the cytoplasmic RTK receptor tails. More than one SH2-containing protein can bind at the same time to an activated RTK, allowing simultaneous activation of multiple intracellular signaling pathways like MAPK/Erk and Akt pathway (Figure 1)

The Erk pathway is activated by a wide range of receptors involved in growth and differentiation including RKT’s. Briefly, a set of adaptors linking the receptor to a guanine exchange factor transducing the signal to small GTP-binding proteins which in turn activate the core unit of cascade. An activated Erk dimer can regulate the cytosol targets and also translocate to the nucleus where it phosphorylates a variety of transcription factors regulating gene expression

The serine/threonine Akt kinase is a proto-oncogene and has a critical regulatory function in cancer progression and insulin metabolism. This pathway is activated by RTK’s and other stimuli that induce PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle

Aberrant activation of RTKs in human cancers is mediated by three principal mechanisms: autocrine activation, chromosomal translocations, gene amplification and RTK overexpression

Several drugs have been developed and approved by the US Food and Drug Administration for treating cancers and other diseases caused by activated RTKs and these drugs fall into two categories, small molecule inhibitors that target the ATP-binding site of the intracellular TKD and monoclonal antibodies that both interfere with RTK activation and target RTK-expressing cells for destruction by the immune system

1.4 The HER Family

The HER family (or ErBb) of receptors comprises the family I of RTKs that includes EGFR, HER2, HER3 and HER4. Each of the receptors is a type I transmembrane protein consisting of a heavily glycosylated ectodomain that contains a ligand binding site, a single transmembrane domain, an intracellular protein-tyrosine kinase catalytic domain (TKD) and a tyrosine-containing cytoplasmic tail One exception is HER3 because this receptor lacks intrinsic tyrosine activity, so the receptor can only initiate signal transduction when dimerized with another HER family member.

http://ebm.sagepub.com/content/236/4/375/F1.large.jpgFigure 1. Schematic representation of a representative RTK, EGFR. After ligand binding occurs phosphorilation of the receptor that leads to activation of signaling pathways (Lee et al. 2011).

In general, growth factor binding to regions I and III in the ectodomain induces a conformational change to convert the receptor ectodomain from a tethered, inactive conformation to an extended, active conformation

The four EGF receptors recognize thirteen different but structurally related growth factors (Figure 2). EGFR is regulated by at least seven different activating ligands in humans: EGF itself, transforming growth factor a (TGF-a), betacellulin (BTC), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (ARG), epiregulin (EPR), and epigen (EGN). Each contains an EGF-like domain that is responsible for receptor binding and activation, with a characteristic pattern of six spatially conserved cysteines. For HER2, no soluble ligand has been identified. This orphan receptor is generally assumed only to be regulated by heterodimerization with other HER family receptors. HER3 and HER4 are regulated by neuregulins in a wide variety of different isoforms that all contain an EGF-like domain. Three of the EGFR ligands previously mentioned (BTC, EPR, and HB-EGF) also bind and activate HER4 and are termed “bispecific” ligands

ErbB

Figure 2. Schematic representation of HER family members with possible ligands and possible pairs of dimmers (Zhang et al. 2007)

Importantly, EGFR and his relatives are known oncogenic drivers in cancer such as lung cancer, breast cancer and glioblastoma and inhibitors of these receptors have been among the most successful examples of targeted cancer therapies to date, including antibody therapeutics (e.g., trastuzumab and cetuximab) and small-molecule tyrosine kinase inhibitors (e.g., erlotinib, gefitinib, lapatinib)

1.5 The HER Family in cervical cancer

Concerning cervical cancer, the expression of EGFR appears to have a direct association with human papillomavirus (HPV) infection, as evidenced by its increasing expression as the grade of intraepithelial neoplasia increases Some studies indicated that EGFR expression is associated with poor response to chemoradiation while other studies have not found such an association with poor prognosis

HER2 is also rarely expressed in the normal surface epithelia of the lower genital tract, with higher HER2 expression in the basal layer compared with the surface layer The degree and frequency of HER2 overexpression in cervical lesions has been directly correlated with the grade of dysplasia or stage of cancer

In squamous cells carcinomas HER3 is known to be expressed in the large majority of those and is correlated with poor prognosis

The role of HER4 in cancer is not well understood however Campiglio et al. suggests that HER3/HER4 heterodimers may be responsible for prolonged activation of mitogen-associated protein kinase (MAPK) that causes cellular proliferation. On the other hand, Feng et al. associates HER4 with cell growth inhibition

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