Implications For Cancer Development Research Articles

Regulation of cell motility by Na+/H+ exchanger NHE1: implications for cancer development

Essential roles of ion channels and transporters in regulation of cell motility have been discovered within the last decade. Here, I review recent evidence from our laboratory and others regarding the roles of the Na+/H+ exchanger NHE1 in cell motility, with particular focus on the implications for cancer metastasis. In many cell types, NHE1 localizes to the leading edge of migrating cells and regulates directional cell motility by mechanisms which include the formation of intra‐ and extracellular pH‐gradients and likely also direct protein‐protein interactions and local cell volume changes. In addition, NHE1 localizes strongly to invadopodia: actin‐rich structures assigned essential roles in invading cells. Here, NHE1 appears to be involved in both invadopodia formation and in their extracellular matrix‐degrading function. NHE1 is upregulated in a wide range of human cancers, and inhibition/knockdown of NHE1 attenuates metastasis in several cancer models. However, under some conditions, NHE1 inhibition/knockdown increases adhesiveness and motility, suggesting that the specific role of NHE1 is context‐dependent. In conclusion, NHE1 plays important roles in controlling cell motility. However, to exploit the obvious potential of interfering with NHE1 function to treat cancer metastasis, greater mechanistic understanding of the mechanisms is needed.Funding: Danish Cancer Society, Danish Research Council

A portrayal of E3 ubiquitin ligases and deubiquitylases in cancer

E3 ubiquitin ligases and deubiquitylating enzymes (DUBs) are the key components of ubiquitin proteasome system which plays a critical role in cellular protein homeostasis. Any shortcoming in their biological roles can lead to various diseases including cancer. The dynamic interplay between ubiquitylation and deubiquitylation determines the level and activity of several proteins including p53, which is crucial for cellular stress response and tumor suppression pathways. In this review, we describe the different types of E3 ubiquitin ligases including those targeting tumor suppressor p53, SCF ligases and RING type ligases and accentuate on biological functions of few important E3 ligases in the cellular regulatory networks. Tumor suppressor p53 level is tightly regulated by multiple E3 ligases including Mdm2, COP1, Pirh2, etc. SCF ubiquitin ligase complexes are key regulators of cell cycle and signal transduction. BRCA1 and VHL RING type ligases function as tumor suppressors and play an important role in DNA repair and hypoxia response respectively. Further, we discuss the biological consequences of deregulation of the E3 ligases and the implications for cancer development. We also describe deubiquitylases which reverse the process of ubiquitylation and regulate diverse cellular pathways including metabolism, cell cycle control and chromatin remodelling. As the E3 ubiquitin ligases and DUBs work in a substrate specific manner, an improved understanding of them can lead to better therapeutics for cancer.

A cyclin without cyclin-dependent kinases: cyclin F controls genome stability through ubiquitin-mediated proteolysis

Cell cycle transitions are driven by the periodic oscillations of cyclins, which bind and activate cyclin-dependent kinases (CDKs) to phosphorylate target substrates. Cyclin F uses a substrate recruitment strategy similar to that of the other cyclins, but its associated catalytic activity is substantially different. Indeed, cyclin F is the founding member of the F-box family of proteins, which are the substrate recognition subunits of Skp1-Cul1-F-box protein (SCF) ubiquitin ligase complexes. Here, we discuss cyclin F function and recently identified substrates of SCF(cyclin)(F) involved in deoxyribonucleotide triphosphate (dNTP) production, centrosome duplication, and spindle formation. We highlight the relevance of cyclin F in controlling genome stability through ubiquitin-mediated proteolysis and the implications for cancer development.

Ambra1 at the crossroad between autophagy and cell death

Autophagy is a self-digesting mechanism responsible for the degradation and recycling of most intracellular macromolecules and the removal of damaged organelles by the lysosome. An impressive number of recent studies have provided key information about the regulation of autophagy and its role in cell survival during nutrient depletion and many other stressful situations. In particular, many evidences have highlighted a crucial role of dysregulated autophagy in oncogenesis. Perturbations of the autophagic pathway have been shown to contribute to tumor development. Moreover, cancer cells have developed several mechanisms that allow them to evade chemotherapy-induced cell death, as well as to use autophagy-associated pathways, to potentiate their survival. In this regard, a complex crosstalk between autophagy and apoptosis has recently emerged; the understanding of the molecular mechanisms regulating this interplay may provide new hints on how to properly modulate these processes to halt cancer. Indeed, key proteins originally thought to be apoptosis-specific inhibitors also block autophagy, while apoptosis proteolytic enzymes hamper autophagy by cleaving autophagy-specific proteins and, in some cases, converting them into proapoptotic factors. This review is focused on the role that Ambra1, a central component of the autophagosome formation machinery, has in the switch between autophagy and apoptosis and its implication in cancer development and chemotherapy resistance.

MiR-205 regulates basement membrane deposition in human prostate: implications for cancer development

The basement membrane (BM) is a layer of specialized extracellular matrix that surrounds normal prostate glands and preserves tissue integrity. Lack or discontinuity of the BM is a prerequisite for tumor cell invasion into interstitial spaces, thus favoring metastasis. Therefore, BM maintenance represents a barrier against cancer development and progression. In the study, we show that miR-205 participates in a network involving ΔNp63α, which is essential for maintenance of the BM in prostate epithelium. At the molecular level, ΔNp63α is able to enhance miR-205 transcription by binding to its promoter, whereas the microRNA can post-transcriptionally limit the amount of ΔNp63α protein, mostly by affecting ΔNp63α proteasomal degradation rather than through a canonical miRNA/target interaction. Functionally, miR-205 is able to control the deposition of laminin-332 and its receptor integrin-β4. Hence, pathological loss of miR-205, as widely observed in prostate cancer, may favor tumorigenesis by creating discontinuities in the BM. Here we demonstrate that therapeutic replacement of miR-205 in prostate cancer (PCa) cells can restore BM deposition and 3D organization into normal-like acinar structures, thus hampering cancer progression.

Functional CSF‐1 receptors are located at the nuclear envelope and activatedviathe p110δ isoform of PI 3‐kinase

Colony stimulating factor-1 (CSF-1) and its receptor (CSF-1R) are key regulators of macrophage biology, and their elevated expression in cancer cells has been linked to poor prognosis. CSF-1Rs are thought to function at the plasma membrane. We show here that functional CSF-1Rs are present at the nuclear envelope of various cell types, including primary macrophages, human cancer cell lines, and primary human carcinomas. In response to CSF-1, added to intact cells or isolated nuclei, nucleus-associated CSF-1R became phosphorylated and triggered the phosphorylation of Akt and p27 inside the nucleus. Extracellularly added CSF-1 was also found to colocalize with nucleus-associated CSF-1Rs. All these activities were found to depend selectively on the activity of the p110δ isoform of phosphoinositide 3-kinase (PI3K). This finding was related to the p110δ-dependent translocation of exogenous CSF-1 to the nucleus-associated CSF-1Rs, correlating with a prominent role of p110δ in activation of the Rab5 GTPase, a key regulator of the endocytic trafficking. siRNA-silencing of Rab5a phenocopied p110δ inactivation and nuclear CSF-1 signaling. Our work demonstrates for the first time the presence of functional nucleus-associated CSF-1Rs, which are activated by extracellular CSF-1 by a mechanism that involves p110δ and Rab5 activity. These findings may have important implications in cancer development.

Role of p38α in apoptosis: implication in cancer development and therapy

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.

Abstract 4632: Sub-cellular distribution and antioxidant potential of plant flavonoid apigenin

Abstract Dietary flavonoids can prevent one third of cancer-related deaths in the United States possessing their ability to reduce oxidative stress which has implications in cancer development. Apigenin (4’,5,7-trihydroxyflavone), a flavone commonly present in plants such as camomilla, rosemary, parsley, celery and wheat germ has shown to possess anticancer properties. Apigenin has been reported to accumulate in various body organs including prostate gland and perturbs cancer development and progression through modulation of various signaling pathways. The cellular distribution of apigenin and its interaction with nucleic acids remains an important challenge for its development as chemopreventive agent. For these studies, we used various human prostate cancer cells viz. DU145, LNCaP and PC-3 and transformed human prostate epithelial RWPE1 cells. Incubation of LNCaP cells with 20 μM apigenin for 6 h exhibited an accumulation of 1.4 nmoles/million cells which was higher than in PC3 and DU145 by factor of 1.79 and 2.41, respectively. Almost similar uptake of apigenin was observed in RWPE1 cells as in LNCaP cells. The kinetics of apigenin uptake in LNCaP cells was estimated with a Km value of 5μmole/L and Vmax of 190 pmoles/million cells/h. Sub-cellular fractionation demonstrated that nuclear matrix retains the highest concentration of apigenin (45.31%), followed by cytosol (23.90%), nuclear membranes (17.86%) and microsomes (12.91%), respectively. Preferential apigenin retention by the nuclear matrix suggests its interaction with the nucleic acids and prompted further studies to determine the interactions of apigenin with DNA by using UV-Vis spectroscopic methods. Studies conducted with 0.25 mM DNA solution with varying concentrations of apigenin from .006 mM to 0.4mM and absorption spectral changes were recorded at 230 nm-450nm range. Detailed spectroscopic analysis of apigenin with DNA exhibited a marked decrease in the absorption intensity at 335 nm proportional to apigenin concentration indicating the possible intercalation of apigenin with DNA. Reciprocal plot analysis showed linearity and the stability of DNA-apigenin adduct with the magnitude of K=3.62×104 M-1. Furthermore, in vitro studies assessing the antioxidant potential of apigenin demonstrated that 0.25 mM DNA solution lost its spectral peak absorbance upon exposure to 15 mM dose of H2O2. However, the presence of apigenin at 0.4 mM and higher concentration prevented H2O2-mediated damage to DNA as indicated by the restoration of the peak absorbance of DNA. Taken together, our studies demonstrate that apigenin is readily taken up by prostate epithelial and cancer cells, has nuclear presence and its intercalation with nucleic acid bases, might be in part, accountable for its chemopreventive and antioxidant activities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4632. doi:10.1158/1538-7445.AM2011-4632

IGF system in cancer

Insulin-like growth factors (IGFs) are important mediators of growth, development, and survival, and have been implicated in the pathogenesis of malignancies. The IGF system is a complex system comprising two growth factors (IGF-I and IGF-II), cell surface receptors (IGF-IR and IGF-IIR), six specific high-affinity binding proteins (IGFBP-1 to IGFBP-6), IGFBP proteases, and several other IGFBP-interacting molecules that regulate and propagate IGF actions in several tissues. IGFs are produced by almost any cell in the body; circulate in more than 1000-fold higher concentrations than most other peptide hormones, such as insulin, and their action is modulated by several binding proteins. Studies have revealed that IGFs may promote cell cycle progression and inhibition of apoptosis either by directly associating with other growth factors or indirectly by interacting with other molecular systems that have an established role in carcinogenesis and cancer promotion, such as steroid hormones and integrins. In addition, studies also suggest that increased serum levels of IGFs and/or altered levels of their binding proteins are associated with increased risk of developing cancers. These data underline the significance of IGFs system in the development of cancer risk, and a potential target for novel anticancer treatments and/or preventative strategies in high-risk groups. The researchers review the IGFs pathway and its implications in cancer development and treatment.

Calpains as potential anti-cancer targets

Introduction: The intracellular signaling cysteine proteases, calpains (specifically the ubiquitous calpains 1 and 2), are involved in numerous physiological and pathological phenomena. Several works have highlighted the implication of calpains in processes crucial for cancer development and progression. For these reasons, calpains are considered by several authors as potential anti-cancer targets.Areas covered: How calpains are implicated in cancer formation and development, how these enzymes are deregulated in cancer cells and how these proteases could be targeted by anti-cancer drugs. Studies published in the last 10 years are focused on.Expert opinion: Targeting calpain activity with specific inhibitors could be a novel approach to limiting development of primary tumors and formation of metastases, by inhibiting tumor cell migration and invasion, which allows dissemination as well as tumor neovascularization, which in turn allows expansion. However, such drugs could interfere with anti-cancer treatments, as ubiquitous calpains play crucial roles in chemotherapy-induced apoptosis. For these reasons, drugs targeting calpains would have to be used selectively to avoid interference with other treatments and physiological processes. Further studies will be required concerning the other members of the calpain family and their potential implication in cancer development before considering treatments targeting their activity.

Trans-splicing in Higher Eukaryotes: Implications for Cancer Development?

Trans-splicing, the possibility of exons from distinct pre-mRNAs to join together, is still a concept in gene expression that is generally regarded of limited significance. However, recent work has provided evidence that in human tumors trans-splicing events may precede chromosomal rearrangements. In fact, it has been suggested that the trans-spliced molecules could act as “guides” that facilitate the genomic translocation. This perspective highlights the development of the ideas of trans-splicing in higher eukaryotes during the last 25 years, from a bizarre phenomenon to a biological event that is attaining stronger recognition.

Non-coding RNAs enter mitosis: functions, conservation and implications

Nuage (or commonly known as chromatoid body in mammals) is a conserved germline-specific organelle that has been linked to the Piwi-interacting RNA (piRNA) pathway. piRNAs are a class of gonadal-specific RNAs that are ~23-29 nucleotides in length and protect genome stability by repressing the expression of deleterious retrotransposons. More recent studies in Drosophila have implicated the piRNA pathway in other functions including canalization of embryonic development, regulation of maternal gene expression and telomere protection. We have recently shown that Vasa (known as Mouse Vasa Homolog in mouse), a nuage component, plays a mitotic role in promoting chromosome condensation and segregation by facilitating robust chromosomal localization of condensin I in the Drosophila germline. Vasa functions together with Aubergine (a PIWI family protein) and Spindle-E/mouse TDRD-9, two other nuage components that are involved in the piRNA pathway, therefore providing a link between the piRNA pathway and mitotic chromosome condensation. Here, we propose and discuss possible models for the role of Vasa and the piRNA pathway during mitosis. We also highlight relevant studies implicating mitotic roles for RNAs and/or nuage in other model systems and their implications for cancer development.

The role of epigenetic transcription repression and DNA methyltransferases in cancer

Epigenetic alterations such as DNA methylation have been implicated in the development and progression of various cancers. DNA methylation consists of the reversible addition of a methyl group to the carbon 5 position of cytosine in CpG dinucleotides and is considered essential for normal embryonic development. However, global genomic hypomethylation and aberrant hypermethylation of regulatory regions of tumor suppressor genes have been associated with chromosomal instability and transcription repression, respectively, providing neoplastic cells with a selective advantage. DNA methyltransferases are the enzymes responsible for the addition of methyl groups to CpG dinucleotides, which, together with histone modifiers, initiate the events necessary for transcription repression to occur. It has been demonstrated that increased expression of DNA methyltransferases may contribute to tumor progression through methylation-mediated gene inactivation in various human cancers. Given their importance, this article reviews the main epigenetic mechanisms for regulating transcription and its implications in cancer development.

Altered VEGF mRNA Stability following Treatments with Immunosuppressive Agents: IMPLICATIONS FOR CANCER DEVELOPMENT

The high incidence of cancer and its aggressive progression is a common and major problem in patients receiving immunosuppressive therapy. The calcineurin inhibitors (CNIs) may have protumorigenic effects and can promote the overexpression of several molecules inducing tumor growth. We have recently demonstrated that CNIs can mediate the transcriptional activation of the angiogenic cytokine vascular endothelial growth factor (VEGF) and promote a rapid progression of human renal cancer. Here, we investigated whether the CNI cyclosporine (CsA) and the mTOR inhibitor rapamycin (RAPA) could alter the mRNA stability of VEGF in 786-0 and Caki-1 renal cancer cells. Following actinomycin D treatment, we observed that CsA increased, whereas RAPA decreased the VEGF mRNA stability as observed by real time PCR. It is established that the mRNA-binding protein HuR may play a critical role in VEGF mRNA stability. By using HuR-siRNA, we found that the knockdown of HuR significantly decreased the CNI-induced VEGF mRNA stability. By Western blot analysis, it has been observed that CNI treatment induced the translocation of HuR from the nucleus to the cytoplasm; CNIs also induced the association between HuR and PKC-delta and promoted the phosphorylation of HuR. Finally, we found that the inhibition of PKC-delta using a dominant negative plasmid significantly decreased the CsA-induced cytoplasmic translocation of HuR and VEGF mRNA stability. Together, targeting the pathways that promote CNI-induced transcription as well as the mRNA stability of VEGF might serve as novel therapeutics for the prevention and treatment of cancer in immunosuppressed patients.

Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death

Adult stem cells (SCs) are at high risk of accumulating deleterious mutations because they reside and self-renew in adult tissues for extended periods. Little is known about how adult SCs sense and respond to DNA damage within their natural niche. Here, using mouse epidermis as a model, we define the functional consequences and the molecular mechanisms by which adult SCs respond to DNA damage. We show that multipotent hair-follicle-bulge SCs have two important mechanisms for increasing their resistance to DNA-damage-induced cell death: higher expression of the anti-apoptotic gene Bcl-2 and transient stabilization of p53 after DNA damage in bulge SCs. The attenuated p53 activation is the consequence of a faster DNA repair activity, mediated by a higher non-homologous end joining (NHEJ) activity, induced by the key protein DNA-PK. Because NHEJ is an error-prone mechanism, this novel characteristic of adult SCs may have important implications in cancer development and ageing.

The Emerging Picture of Human Breast Cancer as a Stem Cell-based Disease

There are increasing data supporting the existence of a cell hierarchy within the mammary gland. At the top or this hierarchy a small population of cells with self-renewal properties maintains the tissue architecture and remodeling, and they are known as stem cells. Also, recent evidences indicate that breast cancer is originated and maintained by its own cancer stem cells reminding the normal mammary gland. The existence of this small population of cells with self-renewal capability has important biological and clinical significances. So, the interpretation of tumors as hierarchical cellular structures has changed our vision of the breast cancer scenario. Here, we review the current knowledge about normal and breast cancer stem cells, and their implications in cancer development, together with their consequences in breast cancer susceptibility, dissemination and treatment response.

Proteus syndrome with syringohydromyelia and arachnoid cyst

The authors make a good review of the main clinical and genetic aspects of Proteus syndrome. They also describe new neuroimaging findings with clinical significance that must be added to the variety of abnormalities in these rare multi-organic neurocutaneous syndrome. With regard to molecular genetics, Zhou et al. [3] reported a boy with congenital hemihypertrophy, epidermoid nevi, macrocephaly, lipomas, arteriovenous malformations, and normal intellect. The patient had the clinical diagnosis of Proteuslike syndrome. Sequence analysis of DNA from peripheral blood revealed heterozygosity for a single base transversion resulting in an Arg 335 to Ter substitution of the phosphatase and tensin homolog (PTEN) gene product, whereas analysis of the DNA from nevus, lipoma, and arteriovenous mass also revealed heterozygosity for Arg 130 to Ter. The former mutation had been reported in patients with Cowden syndrome, whereas the latter mutation had been reported in individuals with Bannayan– Zonana syndrome. The authors postulated that the second hit, Arg 130 to Ter, occurred early in embryonic development and may even represent germline mosaicism. Thus, PTEN may be involved in Proteus-like syndrome with its implications for cancer development in the future. Five unrelated patients with Proteus syndrome had no demonstrable mutations in PTEN. Smith et al. [2] described a 16-month-old male with a de novo 1-bp deletion in the cDNA of the PTEN gene, 507 delC, and classic features of Proteus syndrome, including a left-sided epidermal nevus following the lines of Blaschko, widespread capillary venous malformation on his chest and abdomen, multiple lipoblastomata, disproportionate overgrowth of the right leg with progressive course. They concludedthatthe demonstration ofagermlinePTEN mutationin Proteus syndrome permitted its classification, along with Cowden and Bannayan–Zonana syndromes, as part of the spectrum of PTEN hamartoma–tumor syndromes (PHTS). Thiffault et al. [1] stated that the most plausible suggestion for the genetic basis of Proteus syndrome is the somatic mosaic hypothesis postulated by Happle in 1999, although no somatic mutations in candidate genes had been reported. Because germline mutations in the PTEN gene had been identified in patients with Proteus syndrome, screened affected and unaffected tissue from six patients with Proteus syndrome were done by direct sequencing of genomic DNA for germline or somatic mutations in PTEN or GPC3. No intra-axonic mutations were identified, indicating that neither PTEN nor GPC3 was likely to have a major role in the etiology of Proteus syndrome in this series of cases.

Mutant V600E BRAF Increases Hypoxia Inducible Factor-1α Expression in Melanoma

Mutations in the BRAF serine/threonine kinase gene are frequently found in cutaneous melanomas. Activation of hypoxia inducible factor-1alpha (HIF-1alpha) in response to both hypoxic stress and oncogenic signals has important implications in cancer development and progression. Here, we report that mutant BRAF(V600E) increases HIF-1alpha expression in melanoma cells. Our microarray profiling data in 35 melanoma and melanocyte cell lines showed that HIF-1alpha gene expression was significantly increased in melanomas harboring BRAF(V600E) mutation. Stable suppression of mutant BRAF(V600E) or both wild-type and mutant BRAF(V600E) by RNA interference in melanoma cells resulted in significantly decreased HIF-1alpha expression. Knockdown of mutant BRAF(V600E) induced significant reduction of cell survival and proliferation under hypoxic conditions, whereas knockdown of both wild-type and mutant BRAF(V600E) resulted in further reduction. The effects of BRAF knockdown can be rescued by reintroducing BRAF(V600E) into tumor cells. Transfection of BRAF(V600E) into melanoma cells with wild-type BRAF induced significantly more hypoxic tolerance. Knockdown of HIF-1alpha in melanoma cells resulted in decreased cell survival under hypoxic conditions. Pharmacologic inhibition of BRAF by BAY 43-9006 also resulted in decreased HIF-1alpha expression. Although HIF-1alpha translational rate was not changed, the protein was less stable in BRAF knockdown cells. In additional, von Hippel-Lindau protein expression was significantly increased in BRAF knockdown cells. Our data show for the first time that BRAF(V600E) mutation increases HIF-1alpha expression and melanoma cell survival under hypoxic conditions and suggest that effects of the oncogenic V600E BRAF mutation may be partially mediated through the HIF-1alpha pathway.

BCL2 Family of Apoptosis-Related Genes: Functions and Clinical Implications in Cancer

One of the most effective ways to combat different types of cancer is through early diagnosis and administration of effective treatment, followed by efficient monitoring that will allow physicians to detect relapsing disease and treat it at the earliest possible time. Apoptosis, a normal physiological form of cell death, is critically involved in the regulation of cellular homeostasis. Dysregulation of programmed cell death mechanisms plays an important role in the pathogenesis and progression of cancer as well as in the responses of tumours to therapeutic interventions.Many members of the BCL2 (B-cell CLL/lymphoma 2; Bcl-2) family of apoptosis-related genes have been found to be differentially expressed in various malignancies, and some are useful prognostic cancer biomarkers. We have recently cloned a new member of this family, BCL2L12, which was found to be differentially expressed in many tumours. Most of the BCL2 family genes have been found to play a central regulatory role in apoptosis induction. Results have made it clear that a number of coordinating alterations in the BCL2 family of genes must occur to inhibit apoptosis and provoke carcinogenesis in a wide variety of cancers. However, more research is required to increase our understanding of the extent to which and the mechanisms by which they are involved in cancer development, providing the basis for earlier and more accurate cancer diagnosis, prognosis and therapeutic intervention that targets the apoptosis pathways.In the present review, we describe current knowledge of the function and molecular characteristics of a series of classic but also newly discovered genes of the BCL2 family as well as their implications in cancer development, prognosis and treatment.

Tyrosine Kinase Receptors Signaling Revealed by Global Expression Profiles: Implications for Cancer Biology

Increasing numbers of human diseases involve mutations, misexpression or malfunctioning of receptor protein tyrosine kinases (RTK). In particular, human cancers are often characterized by altered RTK function, due to different genetic causes. Identification of the gene expression program triggered by (RTKs) is essential to clarify the molecular basis of their biological activities. Intracellular signals of RTKs are initiated by specific tyrosines which, when autophosphorylated, recruit signal transducers. How the activation of different signaling pathways is translated into a certain pattern of gene expression is currently unknown. Recently, scientists have tried to answer this question applying DNA microarrays technology using wild-type and mutant RTKs transiently stimulated with their cognate growth factors. The transcriptional response to chronic stimulation of cells upon ectopic expression of oncogenic RTKs has also been investigated through DNA microarrays. The results obtained recently in this field, with their possible implication in cancer development and their impact on cancer diagnosis and treatment will be discussed. Keywords: RTK, oncogene, gene expression profiling, thyroid