PAUF/ZG16B promotes colorectal cancer progression through alterations of the mitotic functions and the Wnt/ß-catenin pathway.

Pancreatic adenocarcinoma upregulated factor (PAUF), also known as ZG16B, was previously found in the secretome of metastatic colorectal cancer cells. Here, we demonstrated the presence of PAUF at the intracellular level and its multiple effects on cancer progression. An initial decline of PAUF expression was observed at early stages of colorectal cancer followed by an increase at the metastatic site. PAUF was located at different cellular compartments: membrane-associated vesicles, endosomes, microtubule-associated vesicles, cell growth cones and the cell nucleus. PAUF loss in two colorectal cancer cell lines caused severe alterations in the cell phenotype and cell cycle, including tetraploidy, extensive genomic alterations, micronuclei and increased apoptosis. An exhaustive analysis of the PAUF interactome using different proteomic approaches revealed the presence of multiple components of the cell cycle, mitotic checkpoint, Wnt pathway and intracellular transport. Among the interacting proteins we found ZW10, a moonlighting protein with a dual function in membrane trafficking and mitosis. In addition, PAUF silencing was associated to APC loss and increased ß-catenin nuclear expression. Altogether, our results suggest that PAUF depletion increases aneuploidy, promotes apoptosis and activates the Wnt/ß-catenin pathway in colorectal cancer cells facilitating cancer progression. In summary, PAUF behaves as a multifunctional protein, with different roles in cancer progression according to the extra- or intracellular expression, suggesting a therapeutic value for colorectal cancer.

Nutritionally modifiable prognostic biomarkers in colorectal cancer survivors after diagnosis / Biomarcadores de pronóstico modificables nutricionalmente en el paciente con cáncer colorrectal tras el diagnóstico de la enfermedad

Introduction :Colorectal cancer (CRC) is the second most common cancer in the Western world. About one million of new CRC cases are diagnosed per year. The survival rate of patients with CRC changes widely, even among patients with the same tumor histology. This is possibly due to the impact of environmental factors on tumor development. The diet is the most important among these factors. It is known that nutrition can modify the risk of CRC. However, the role that nutrition plays in the risk of recurrence or survival in patients with CRC is not known with accuracy. Objetive: The objective of this review was to try to clarify this fact. Material and methods: Collecting the data obtained as of today in the epidemiological studies of association among recurrence, survival or mortality risk of CRC; and vitamins and the body mass index (BMI), to develop a series of nutritional advices to patients. Conclusions: Thanks to the studies discussed in this work, we could conclude that: BMI, retinol and vitamin D, and in some cases folic acid, at the time of disease diagnosis, operate like recurrence and survival prognosis markers in CRC.

Introducción: el cáncer colorrectal (CCR) es el segundo cáncer más frecuente en el mundo occidental, de tal manera que se diagnostican cerca de 1 millón de casos nuevos por año. La tasa de supervivencia de pacientes con CCR varía ampliamente, aun entre pacientes con el mismo tumor histológico. Esto posiblemente es debido al impacto de los factores ambientales sobre el desarrollo tumoral. Dentro de estos factores, destaca la dieta. Se conoce que la nutrición puede modificar el riesgo de padecer CCR. Sin embargo, no se conoce con precisión el papel que desempeña la nutrición en el riesgo de recurrencia o supervivencia en pacientes con CCR. Objetivo: el objetivo de esta revisión fue tratar de esclarecer el papel que desempeña la nutrición en el riesgo de recurrencia o supervivencia en pacientes con CCR. Material y métodos: recopilación de los datos obtenidos hasta el momento en los estudios epidemiológicos más recientes, de la asociación entre recurrencia, supervivencia o riesgo de mortalidad al CCR; y las vitaminas y el índice de masa corporal (IMC), con el fin de elaborar una serie de consejos nutricionales a estos pacientes. Conclusiones: gracias a los estudios comentados se puede concluir que el IMC y el nivel de vitamina D, retinol y en algunos casos el del ácido fólico, en el momento del diagnóstico de la enfermedad, funcionan como marcadores de pronóstico de recurrencia y supervivencia al CCR.

Biomarcadores de pronóstico modificables nutricionalmente en el paciente con cáncer colorrectal tras el diagnóstico de la enfermedad / Nutritionally modifiable prognostic biomarkers in colorectal cancer survivors after diagnosis

Introducción: el cáncer colorrectal (CCR) es el segundo cáncer más frecuente en el mundo occidental, de tal manera que se diagnostican cerca de 1 millón de casos nuevos por año. La tasa de supervivencia de pacientes con CCR varía ampliamente, aun entre pacientes con el mismo tumor histológico. Esto posiblemente es debido al impacto de los factores ambientales sobre el desarrollo tumoral. Dentro de estos factores, destaca la dieta. Se conoce que la nutrición puede modificar el riesgo de padecer CCR. Sin embargo, no se conoce con precisión el papel que desempeña la nutrición en el riesgo de recurrencia o supervivencia en pacientes con CCR. Objetivo: el objetivo de esta revisión fue tratar de esclarecer el papel que desempeña la nutrición en el riesgo de recurrencia o supervivencia en pacientes con CCR. Material y métodos: recopilación de los datos obtenidos hasta el momento en los estudios epidemiológicos más recientes, de la asociación entre recurrencia, supervivencia o riesgo de mortalidad al CCR; y las vitaminas y el índice de masa corporal (IMC), con el fi n de elaborar una serie de consejos nutricionales a estos pacientes. Conclusiones: gracias a los estudios comentados se puede concluir que el IMC y el nivel de vitamina D, retinol y en algunos casos el del ácido fólico, en el momento del diagnóstico de la enfermedad, funcionan como marcadores de pronóstico de recurrencia y supervivencia al CCR (AU)

Introduction: Colorectal cancer (CRC) is the second most common cancer in the Western world. About one million of new CRC cases are diagnosed per year. The survival rate of patients with CRC changes widely, even among patients with the same tumor histology. This is possibly due to the impact of environmental factors on tumor development. The diet is the most important among these factors. It is known that nutrition can modify the risk of CRC. However, the role that nutrition plays in the risk of recurrence or survival in patients with CRC is not known with accuracy. Objetive: The objective of this review was to try to clarify this fact. Material and methods: Collecting the data obtained as of today in the epidemiological studies of association among recurrence, survival or mortality risk of CRC; and vitamins and the body mass index (BMI), to develop a series of nutritional advices to patients. Conclusions: Thanks to the studies discussed in this work, we could conclude that: BMI, retinol and vitamin D, and in some cases folic acid, at the time of disease diagnosis, operate like recurrence and survival prognosis markers in CRC (AU)

VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers.

We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VE-cadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE-cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and α2ß1 integrin, with the RGD motifs found to directly affect ß1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VE-cadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE-cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers.

An RGD motif present in cadherin 17 induces integrin activation and tumor growth.

Little is known about the mechanism of integrin activation by cadherin 17 (CDH17). Here we observed the presence of a tri-peptide motif, RGD, in domain 6 of the human CDH17 sequence and other cadherins such as cadherin 5 and cadherin 6. The use of CDH17 RAD mutants demonstrated a considerable decrease of proliferation and adhesion in RKO and KM12SM colon cancer cells. Furthermore, RGD peptides inhibited the adhesion of both cell lines to recombinant CDH17 domain 6. The RGD motif added exogenously to the cells provoked a change in ß1 integrin to an active, high-affinity conformation and an increase in focal adhesion kinase and ERK1/2 activation. In vivo experiments with Swiss nude mice demonstrated that cancer cells expressing the CDH17 RAD mutant showed a considerable delay in tumor growth and liver homing. CDH17 RGD effects were also active in pancreatic cancer cells. Our results suggest that α2ß1 integrin interacts with two different ligands, collagen IV and CDH17, using two different binding sites. In summary, the RGD binding motif constitutes a switch for integrin pathway activation and shows a novel capacity of CDH17 as an integrin ligand. This motif could be targeted to avoid metastatic dissemination in tumors overexpressing CDH17 and other RGD-containing cadherins.