RESUMEN

Despite decades of research presenting insulin-like growth factor-1 receptor (IGF1R) as an attractive target for cancer therapy, IGF1R inhibitors ultimately failed in clinical trials. This was surprising due to the known cancer-promoting functions of IGF1R, including stimulation of cell invasion, proliferation, and survival. Discourse in the literature has acknowledged that a lack of patient stratification may have impacted the success of IGF1R-inhibitor trials. This argument alludes to the possibility that IGF1R function may be contingent on tumor type and cellular composition. Looking into the known roles of IGF1R, it becomes clear that this receptor interacts with a multitude of different proteins and even has tumor-suppressing functions. IGF1R is implicated in both cell-cell and cell-surface adhesion dynamics, and the effects of either IGF1R downregulation or pharmacological inhibition on cellular adhesion remain poorly understood. In turn, adhesion receptors modulate IGF1R signaling. In addition, our understanding of IGF1R function in tumor-associated immune and stromal cells is lacking, which could contribute to the overwhelming failure of IGF1R inhibitors in the clinic. In this review, we re-investigate clinical trial data to make connections between the failure of these drugs in human cancer patients and the understudied facets of IGF1R function. We describe lesser-known and potentially tumor-suppressive functions of IGF1R that include promoting cell-cell adhesion through E-cadherin, augmenting a pro-inflammatory macrophage phenotype, and stimulating B cells to produce immunoglobulins. We also highlight the important role of adhesion receptors in regulating IGF1R function, and we use this information to infer stratification criteria for selecting patients that might benefit from IGF1R inhibitors.

Asunto(s)

Factor I del Crecimiento Similar a la Insulina , Neoplasias , Receptor IGF Tipo 1 , Humanos , Cadherinas/genética , Cadherinas/metabolismo , Cadherinas/farmacología , Línea Celular Tumoral , Proliferación Celular , Factor I del Crecimiento Similar a la Insulina/metabolismo , Integrinas , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transducción de Señal

RESUMEN

The immunoglobulin family cell adhesion receptor L1 is induced in CRC cells at the invasive front of the tumor tissue, and confers enhanced proliferation, motility, tumorigenesis, and liver metastasis. To identify putative tumor suppressors whose expression is downregulated in L1-expressing CRC cells, we blocked the L1-ezrin-NF-κB signaling pathway and searched for genes induced under these conditions. We found that TFF1, a protein involved in protecting the mucus epithelial layer of the colon, is downregulated in L1-expressing cells and displays characteristics of a tumor suppressor. Overexpression of TFF1 in L1-transfected human CRC cells blocks the pro-tumorigenic and metastatic properties conferred by L1 by suppressing NF-κB signaling. Immunohistochemical analyses revealed that human CRC tissue samples often lose the expression of TFF1, while the normal mucosa displays TFF1 in goblet cells. Identifying TFF1 as a tumor suppressor in CRC cells could provide a novel marker for L1-mediated CRC development and a potential target for therapy.

RESUMEN

Previously, we showed that mice treated with cyclophosphamide (CTX) 4 days before intravenous injection of breast cancer cells had more cancer cells in the lung at 3 h after cancer injection than control counterparts without CTX. At 4 days after its injection, CTX is already excreted from the mice, allowing this pre-treatment design to reveal how CTX may modify the lung environment to indirectly affect cancer cells. In this study, we tested the hypothesis that the increase in cancer cell abundance at 3 h by CTX is due to an increase in the adhesiveness of vascular wall for cancer cells. Our data from protein array analysis and inhibition approach combined with in vitro and in vivo assays support the following two-prong mechanism. (1) CTX increases vascular permeability, resulting in the exposure of the basement membrane (BM). (2) CTX increases the level of matrix metalloproteinase-2 (MMP-2) in mouse serum, which remodels the BM and is functionally important for CTX to increase cancer abundance at this early stage. The combined effect of these two processes is the increased accessibility of critical protein domains in the BM, resulting in higher vascular adhesiveness for cancer cells to adhere. The critical protein domains in the vascular microenvironment are RGD and YISGR domains, whose known binding partners on cancer cells are integrin dimers and laminin receptor, respectively.

Asunto(s)

Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/farmacología , Metaloproteinasa 2 de la Matriz/sangre , Microambiente Tumoral/efectos de los fármacos , Animales , Membrana Basal/efectos de los fármacos , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Permeabilidad Capilar/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Integrina beta1/metabolismo , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/secundario , Masculino , Ratones , Ratones Noqueados , Dominios Proteicos , Microambiente Tumoral/fisiología

RESUMEN

Although malignant ascites (MAs) are known to contribute to various aspects of ovarian cancer progression, knowledge regarding their role in the adhesion of cancer cells to normal peritoneal cells is incomplete. Here, we compared the effect of MAs and benign ascites (BAs) on the adhesion of A2780 and OVCAR-3 cancer cells to omentum-derived peritoneal mesothelial cells (PMCs) and peritoneal fibroblasts (PFBs). The results showed that MAs stimulated the adhesion of A2780 and OVCAR-3 cells to PMCs and PFBs more efficiently than did BAs, and the strongest binding occurred when both cancer and normal cells were exposed to the fluid. Intervention studies showed that MAs-driven adhesion of A2780 cells to PMCs/PFBs depends on the presence of TGF-ß1 and HGF, whereas binding of OVCAR-3 cells was mediated by TGF-ß1, GRO-1, and IGF-1. Moreover, MAs upregulated α5ß1 integrin expression on PFBs but not on PMCs or cancer cells, vimentin expression in all cells tested, and ICAM-1 only in cancer cells. When integrin-linked kinase was neutralized in PMCs or PFBs, cancer cell adhesion to PMCs and PFBs decreased. Collectively, our report shows that MAs may contribute to the early stages of ovarian cancer metastasis by modulating the proadhesive interplay between normal and cancer cells.

Asunto(s)

Ascitis/metabolismo , Ascitis/patología , Adhesión Celular/fisiología , Neoplasias Ováricas/metabolismo , Apoptosis/fisiología , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Células Cultivadas , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Neoplasias Ováricas/patología , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/patología , Peritoneo/metabolismo , Peritoneo/patología

RESUMEN

The in vitro cell adhesion assay is a quantitative method for measuring selective cell adhesion to specific proteins. Traditionally, cell adhesion assays employ purified protein immobilized on a solid glass or plastic surface. Here, we describe a transient 293T cell transfection-based cell adhesion assay to study selective cell adhesion of a specific cell type to a protein of interest. In this protocol, 293T cells are transfected with a mammalian expression plasmid containing mSiglec1 cDNA or an empty plasmid as a mock control and are then cultured to form a monolayer. Subsequently, these Siglec1-expressing and mock-transfected 293T cell monolayers are used for cell adhesion assays with GFP-expressing B16F10 cells. The number of GFP+ cancer cells adhering to each 293T monolayer is a quantitative mean to compare the selective adhesiveness of cancer cells to Siglec1. This method eliminates the need to express and purify the protein of interest to perform in vitro cell adhesion assays and can easily be performed with difficult-to-purify proteins while maintaining their native in situ structure.

RESUMEN

Cancer is a global multifactorial disease consisting of over 200 types of cancers. It is well recognized that primary prevention is an effective way to fight cancers by using natural polyphenolic anticancer foods, vegetables, and fruits, avoiding exposure to the carcinogenic environment, smoking cessation, and through lifestyle modifications. The present review provides up-todate information on the effects and functions of pomegranate juice and its bioactive components on the most widespread six cancer types. Pomegranate contains important polyphenolic compounds, such as ellagitannins and punicalagin, with strong antioxidant ability for scavenging free radicals and producing metal-chelates in the biological tissues. The in vitro and in vivo studies suggests that antioxidant and anti-inflammation properties of pomegranate constitute have major antimutagenic and antiproliferative activities for regulating gene expression, modulating cellular mechanisms, and limiting the ability of cancers to metastasize. A limited number of clinical studies have suggested that pomegranate ingredients have the potential for the prevention and treatment of cancer, especially colorectal and prostate cancer. In cancer therapy, it remains a clinical dilemma to hit the right target without inducing side effects. The costly anticancer chemotherapies are often associated with drug resistance and serious side effects in vital organs and noncancerous neighboring cells. It appears that the pomegranate-based phytotherapy would be affordable and cost-effective for next-generation non-pharmacologic anticancer remedies with lesser side effects. However, well-designed, randomized, double-blind, and multi-center studies are needed to establish the long-term safety, efficacy, and dose schedules for orally deliverable pomegranate formulations.

Asunto(s)

Lythraceae , Neoplasias , Granada (Fruta) , Antioxidantes , Frutas , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & control , Extractos Vegetales , Ensayos Clínicos Controlados Aleatorios como Asunto

RESUMEN

In this data article, the potential role of p53 tumor suppressor gene (p53) on the attachment ability of MCF-7 breast cancer cells was investigated. In our main article, "IGF-I/ EGF and E2 signaling crosstalk through IGF-IR conduit point affect breast cancer cell adhesion" (K. Voudouri, D. Nikitovic, A. Berdiaki, D. Kletsas, N.K. Karamanos, G.N. Tzanakakis, 2016) [1], we describe the key role of IGF-IR in breast cancer cell adhesion onto fibronectin (FN). p53 tumor suppressor gene is a principal regulator of cancer cell proliferation. Various data have demonstrated an association between p53 and IGF-IR actions on cell growth through its' putative regulation of IGF-IR expression. According to our performed experiments, p53 does not modify IGF-IR expression and does not affect basal MCF-7 cells adhesion onto FN. Moreover, technical details about the performance of adhesion assay onto the FN substrate were provided.

RESUMEN

Loss or downregulation of the tumor-suppressor KAI1 correlates with poor cancer patient prognosis. KAI1 functions by interacting with other proteins, including integrin cell adhesion and signaling receptors. We previously showed that KAI1 physically and functionally crosstalks with the tumor-biologically relevant integrin αvß3, thereby suppressing ovarian cancer cell migration and proliferation. Interestingly, in metastases, a KAI1 splice variant had been identified, indicating poor patient prognosis. Thus, we here characterized differential effects of the two KAI1 proteins upon their cellular restoration. Opposite to KAI1, KAI1-splice reduced αvß3-mediated cell adhesion, thereby inducing cell migration. This was accompanied by elevated αvß3 levels and drastically elevated focal adhesion kinase activation, however, without any obvious colocalization with αvß3, as observed for KAI1. Moreover, codistribution of KAI1 with the cell/cell-adhesion molecule E-cadherin was abrogated in KAI1-splice. Whereas KAI1 diminished cell proliferative activity, KAI1-splice prominently enhanced cell proliferation concomitant with elevated transcription and cell-surface expression of the epidermal growth factor receptor. Thus KAI1-splice does not only counteract the tumor-suppressive actions of KAI1, but - beyond that - promotes αvß3-mediated biological functions in favor of tumor progression and metastasis.

Asunto(s)

Integrina alfaVbeta3/metabolismo , Proteína Kangai-1/genética , Empalme Alternativo , Cadherinas/metabolismo , Adhesión Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Integrina alfaVbeta3/genética , Proteína Kangai-1/metabolismo , Microscopía por Video , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , Imagen de Lapso de Tiempo

RESUMEN

Random homozygous gene perturbation (RHGP), in combination with liver sinusoidal endothelial cell (LSEC) adhesion screening of clonal colon cancer cells with perturbed genes, was used to identify genes contributing to the hepatic microvascular adhesion of colon cancer cells. Plasmid vector encoding transactivator and gene search vector were transfected into HT-29 human colorectal cancer cells to create a HT-29 RHGP cell library; the adhesion of these library cells to primary cultured mouse LSEC significantly decreased in the presence of RSL1 ligand (inducer), indicating that most of the genes contributing to HT-29 adhesion to LSEC were altered. Next, HT-29 RHGP cell library fractions with upregulated or silenced LSEC adhesion-related genes were isolated. Around 160 clones having altered expression in LSEC adhesion-related genes were obtained, and nine relevant protein-coding genes were identified. Some were proadhesive genes detected because of their overexpression in adherent HT-29 cells (DGCR8 and EFEMP1 genes) and their silenced status in nonadherent HT-29 cells (DGKE, DPY19L1, KIAA0753, PVR and USP11 genes). Others were antiadhesive genes detected because of their overexpression in nonadherent HT-29 cells (ITPKC gene) and their silenced status in adherent HT-29 cells (PPP6R2 gene). Silencing of PVR, DGCR8 and EFEMP1 genes decreased adhesion to LSEC and hepatic microvascular retention of HT-29 cells. The results conclude that RHGP was a valuable strategy for the discovery of mechanisms regulating microvascular adhesion of circulating colon cancer cells before hepatic metastasis formation. Identified genes may contribute to understand the metastatic process of colon cancer and to discovering molecular targets for hepatic metastasis therapeutics.

Asunto(s)

Biomarcadores de Tumor/genética , Adhesión Celular/genética , Neoplasias del Colon/genética , Células Endoteliales/metabolismo , Neoplasias Hepáticas/genética , Hígado/irrigación sanguínea , Animales , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Western Blotting , Células Cultivadas , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Células Endoteliales/patología , Citometría de Flujo , Perfilación de la Expresión Génica , Células HT29 , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

Increased concentrations of free circulating galectin-3 are commonly seen in the blood circulation of patients with many types of cancers including colorectal cancer. Recent studies have shown that changes in circulating galectin-3 levels in cancer patients may contribute significantly to the metastatic spread of disseminating cancer cells by enhancing their ability to adhere to blood vessel endothelium and by helping their avoidance of immune surveillance. Thus, targeting the galectin-3 actions in the circulation may hold significant promise for future development of novel therapeutic agents to prevent metastasis and reduce cancer-associated fatality.