Teneurins: Role in Cancer and Potential Role as Diagnostic Biomarkers and Targets for Therapy

Teneurins have been identified in vertebrates as four different genes (TENM1-4), coding for membrane proteins that are mainly involved in embryonic and neuronal development. Genetic studies have correlated them with various diseases, including developmental problems, neurological disorders and congenital general anosmia. There is some evidence to suggest their possible involvement in cancer initiation and progression, and drug resistance. Indeed, mutations, chromosomal alterations and the deregulation of teneurins expression have been associated with several tumor types and patient survival. However, the role of teneurins in cancer-related regulatory networks is not fully understood, as both a tumor-suppressor role and pro-tumoral functions have been proposed, depending on tumor histotype. Here, we summarize and discuss the literature data on teneurins expression and their potential role in different tumor types, while highlighting the possibility of using teneurins as novel molecular diagnostic and prognostic biomarkers and as targets for cancer treatments, such as immunotherapy, in some tumors

The new paradigm of Network Medicine to analyse breast cancer phenotypes

Breast cancer (BC) is a heterogeneous and complex disease as witnessed by the existence of different subtypes and clinical characteristics that poses significant challenges in disease management. The complexity of this tumor may rely on the highly interconnected nature of the various biological processes as stated by the new paradigm of Network Medicine. We explored The Cancer Genome Atlas (TCGA)-BRCA data set, by applying the network-based algorithm named SWItch Miner, and mapping the findings on the human interactome to capture the molecular interconnections associated with the disease modules. To characterize BC phenotypes, we constructed protein–protein interaction modules based on “hub genes”, called switch genes, both common and specific to the four tumor subtypes. Transcriptomic profiles of patients were stratified according to both clinical (immunohistochemistry) and genetic (PAM50) classifications. 266 and 372 switch genes were identified from immunohistochemistry and PAM50 classifications, respectively. Moreover, the identified switch genes were functionally characterized to select an interconnected pathway of disease genes. By intersecting the common switch genes of the two classifications, we selected a unique signature of 28 disease genes that were BC subtype-independent and classification subtype-independent. Data were validated both in vitro (10 BC cell lines) and ex vivo (66 BC tissues) experiments. Results showed that four of these hub proteins (AURKA, CDC45, ESPL1, and RAD54L) were over-expressed in all tumor subtypes. Moreover, the inhibition of one of the identified switch genes (AURKA) similarly affected all BC subtypes. In conclusion, using a network-based approach, we identified a common BC disease module which might reflect its pathological signature, suggesting a new vision to face with the disease heterogeneity

Extended flow cytometry characterization of normal bone marrow progenitor cells by simultaneous detection of aldehyde dehydrogenase and early hematopoietic antigens: implication for erythroid differentiation studies

<p>Abstract</p> <p>Background</p> <p>Aldehyde dehydrogenase (ALDH) is a cytosolic enzyme highly expressed in hematopoietic precursors from cord blood and granulocyte-colony stimulating factor mobilized peripheral blood, as well as in bone marrow from patients with acute myeloblastic leukemia. As regards human normal bone marrow, detailed characterization of ALDH⁺cells has been addressed by one single study (Gentry <it>et al</it>, 2007). The goal of our work was to provide new information about the dissection of normal bone marrow progenitor cells based upon the simultaneous detection by flow cytometry of ALDH and early hematopoietic antigens, with particular attention to the expression of ALDH on erythroid precursors. To this aim, we used three kinds of approach: i) multidimensional analytical flow cytometry, detecting ALDH and early hematopoietic antigens in normal bone marrow; ii) fluorescence activated cell sorting of distinct subpopulations of progenitor cells, followed by <it>in vitro </it>induction of erythroid differentiation; iii) detection of ALDH⁺cellular subsets in bone marrow from pure red cell aplasia patients.</p> <p>Results</p> <p>In normal bone marrow, we identified three populations of cells, namely ALDH⁺CD34⁺, ALDH^-CD34⁺and ALDH⁺CD34^-(median percentages were 0.52, 0.53 and 0.57, respectively). As compared to ALDH^-CD34⁺cells, ALDH⁺CD34⁺cells expressed the phenotypic profile of primitive hematopoietic progenitor cells, with brighter expression of CD117 and CD133, accompanied by lower display of CD38 and CD45RA. Of interest, ALDH⁺CD34^-population disclosed a straightforward erythroid commitment, on the basis of three orders of evidences. First of all, ALDH⁺CD34^-cells showed a CD71^bright, CD105⁺, CD45^-phenotype. Secondly, induction of differentiation experiments evidenced a clear-cut expression of glycophorin A (CD235a). Finally, ALDH⁺CD34^-precursors were not detectable in patients with pure red cell aplasia (PRCA).</p> <p>Conclusion</p> <p>Our study, comparing surface antigen expression of ALDH⁺/CD34⁺, ALDH^-/CD34⁺and ALDH⁺/CD34^-progenitor cell subsets in human bone marrow, clearly indicated that ALDH⁺CD34^-cells are mainly committed towards erythropoiesis. To the best of our knowledge this finding is new and could be useful for basic studies about normal erythropoietic differentiation as well as for enabling the employment of ALDH as a red cell marker in polychromatic flow cytometry characterization of bone marrow from patients with aplastic anemia and myelodysplasia.</p

Role and Involvement of TENM4 and miR-708 in Breast Cancer Development and Therapy

Teneurin 4 (TENM4) is a transmembrane protein that is codified by the ODZ4 gene and is involved in nervous system development, neurite outgrowth, and neuronal differentiation. In line with its involvement in the nervous system, TENM4 has also been implicated in several mental disorders such as bipolar disorder, schizophrenia, and autism. TENM4 mutations and rearrangements have recently been identified in a number of tumors. This, combined with impaired expression in tumors, suggests that it may potentially be involved in tumorigenesis. Most of the TENM4 mutations that are observed in tumors occur in breast cancer, in which TENM4 plays a role in cells&rsquo; migration and stemness. However, the functional role that TENM4 plays in breast cancer still needs to be better evaluated, and further studies are required to better understand the involvement of TENM4 in breast cancer progression. Herein, we review the currently available data for TENM4&prime;s role in breast cancer and propose its use as both a novel target with which to ameliorate patient prognosis and as a potential biomarker. Moreover, we also report data on the tumorigenic role of miR-708 deregulation and the possible use of this miRNA as a novel therapeutic molecule, as miR-708 is spliced out from TENM4 mRNA