Diaphanous-related formin 1 as a target for tumor therapy

2016 ◽  
Vol 44 (5) ◽  
pp. 1289-1293 ◽  
Author(s):  
Yuan-Na Lin ◽  
Sabine Windhorst
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Colon Carcinoma ◽  
Chromosome Segregation ◽  
Prostate Carcinoma ◽  
Tumor Therapy ◽  
Metastatic Potential ◽  
Carcinoma Cells ◽  
Colon Carcinoma Cells ◽  
Chromosome Alignment

Formins nucleate actin and stabilize microtubules (MTs). Expression of the formin Diaphanous homolog 1 (DIAPH1) is increased in malignant colon carcinoma cells, while expression of DIAPH3 is up-regulated in breast and prostate carcinoma cells. Both DIAPH1 isoforms are required to stabilize interphase MTs of cancer cells, and it has been shown that loss of this function decreases the metastatic potential of these cells. Moreover, depletion of DIAPH3 increases the sensitivity of breast and prostate carcinoma cells to taxanes. In contrast with DIAPH1 + 3, DIAPH2 regulates metaphase MTs of tumor cells by stabilizing binding of kinetochore MTs to chromosomes. Depletion of DIAPH2 impairs chromosome alignment, thus proper chromosome segregation during mitosis. In summary, expression of DIAPH formins in tumor cells is essential for stabilizing interphase or metaphase MTs, respectively. Thus, it would be very interesting to analyze if tumor cells exhibiting low DIAPH expression are more sensitive to taxanes than those with high DIAPH expression.

The PVT gene frequently amplifies with MYC in tumor cells

1989 ◽  
Vol 9 (3) ◽  
pp. 1148-1154
Author(s):  
E Shtivelman ◽  
J M Bishop
Keyword(s):  
Tumor Cells ◽  
Colon Carcinoma ◽  
Cell Lines ◽  
Human Colon ◽  
Carcinoma Cells ◽  
Colon Carcinoma Cells ◽  
Human Colon Carcinoma ◽  
Intron 1 ◽  
Exon 1 ◽  
Additional Portion

The line of human colon carcinoma cells known as COLO320-DM contains an amplified and abnormal allele of the proto-oncogene MYC (DMMYC). Exon 1 and most of intron 1 of MYC have been displaced from DMMYC by a rearrangement of DNA. The RNA transcribed from DMMYC is a chimera that begins with an ectopic sequence of 176 nucleotides and then continues with exons 2 and 3 of MYC. The template for the ectopic sequence represents exon 1 of a gene known as PVT, which lies 50 kilobase pairs downstream of MYC. We encountered three abnormal configurations of MYC and PVT in the cell lines analyzed here: (i) amplification of the genes, accompanied by insertion of exon 1 and an undetermined additional portion of PVT within intron 1 of MYC to create DMMYC; (ii) selective deletion of exon 1 of PVT from amplified DNA that contains downstream portions of PVT and an intact allele of MYC; and (iii) coamplification of MYC and exon 1 of PVT, but not of downstream portions of PVT. We conclude that part or all of PVT is frequently amplified with MYC and that intron 1 of PVT represents a preferred boundary for amplification affecting MYC.

scholarly journals Improved Activation toward Primary Colorectal Cancer Cells by Antigen-Specific Targeting Autologous Cytokine-Induced Killer Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Claudia Schlimper ◽  
Andreas A. Hombach ◽  
Hinrich Abken ◽  
Ingo G. H. Schmidt-Wolf
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Colon Carcinoma ◽  
Ex Vivo ◽  
Carcinoma Cells ◽  
Adoptive Therapy ◽  
Cik Cells ◽  
Colon Carcinoma Cells ◽  
Colorectal Cancer Patients

Adoptive therapy of malignant diseases with cytokine-induced killer (CIK) cells showed promise in a number of trials; the activation of CIK cells from cancer patients towards their autologous cancer cells still needs to be improved. Here, we generated CIK cellsex vivofrom blood lymphocytes of colorectal cancer patients and engineered those cells with a chimeric antigen receptor (CAR) with an antibody-defined specificity for carcinoembryonic antigen (CEA). CIK cells thereby gained a new specificity as defined by the CAR and showed increase in activation towards CEA+colon carcinoma cells, but less in presence of CEA−cells, indicated by increased secretion of proinflammatory cytokines. Redirected CIK activation was superior by CAR-mediated CD28-CD3ζ than CD3ζ signaling only. CAR-engineered CIK cells from colon carcinoma patients showed improved activation against their autologous, primary carcinoma cells from biopsies resulting in more efficient tumour cell lysis. We assume that adoptive therapy with CAR-modified CIK cells shows improved selectivity in targeting autologous tumour lesions.

scholarly journals Podocalyxin-like protein is an E-/L-selectin ligand on colon carcinoma cells: comparative biochemical properties of selectin ligands in host and tumor cells

2009 ◽  
Vol 296 (3) ◽  
pp. C505-C513 ◽  
Author(s):  
Susan N. Thomas ◽  
Ronald L. Schnaar ◽  
Konstantinos Konstantopoulos
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Colon Carcinoma ◽  
Carcinoma Cells ◽  
Host Cells ◽  
High Endothelial Venules ◽  
Colon Carcinoma Cells ◽  
Selectin Ligands ◽  
Selectin Ligand ◽  
Selectin Binding

Selectins facilitate metastasis and tumor cell arrest in the microvasculature by mediating binding of selectin-expressing host cells to ligands on tumor cells. We recently identified CD44 variant isoforms as functional P-, but not E-/L-, selectin ligands on colon carcinoma cells. Furthermore, a ∼180-kDa sialofucosylated glycoprotein(s) mediated selectin binding in CD44-knockdown cells. Using immunoaffinity chromatography and tandem mass spectrometry, we identify podocalyxin-like protein (PCLP) as an alternative selectin ligand. Blot rolling and cell-free flow-based adhesion assays disclose that PCLP on LS174T colon carcinoma cells possesses E-/L-, but not P-, selectin binding activity. The selectin-binding determinants on LS174T PCLP are non-MECA-79-reactive sialofucosylated structures displayed on O-linked glycans, distinct from the MECA-79-reactive O-glycans on PCLP expressed by high endothelial venules, which is an L-selectin ligand. PCLP on CD44-knockdown LS174T cells exhibits higher HECA-452 immunoreactivity than PCLP on wild-type cells, suggesting that PCLP functions as an alternative acceptor for selectin-binding glycans. The enhanced expression of HECA-452 reactivity on PCLP from CD44-knockdown cells correlates with the increased avidity of PCLP for E- but not L-selectin. The novel finding that PCLP is an E-/L-selectin ligand on carcinoma cells offers a unifying perspective on the apparent enhanced metastatic potential associated with tumor cell PCLP overexpression and the role of selectins in metastasis.

Expression of the JE/MCP-1 gene suppresses metastatic potential in murine colon carcinoma cells

1994 ◽  
Vol 39 (4) ◽  
pp. 231-238 ◽  
Author(s):  
Rakesh K. Singh ◽  
Keping Xie ◽  
Mordechai Gutman ◽  
Karen K. Berry ◽  
Corazon D. Bucana ◽  
...  
Keyword(s):  
Colon Carcinoma ◽  
Metastatic Potential ◽  
Carcinoma Cells ◽  
Colon Carcinoma Cells ◽  
Murine Colon Carcinoma ◽  
Murine Colon

CEA and NCA Expressed by Colon Carcinoma Cells Affect their Interaction with and Lysability by Activated Lymphocytes

1992 ◽  
Vol 7 (3) ◽  
pp. 143-147 ◽  
Author(s):  
L. Rivoltini ◽  
G. Cattoretti ◽  
F. Arienti ◽  
A. Mastroianni ◽  
G. Parmiani
Keyword(s):  
Tumor Cells ◽  
Adhesion Molecules ◽  
Colon Carcinoma ◽  
Interleukin 2 ◽  
Carcinoma Cells ◽  
Soluble Antigen ◽  
Dependent Manner ◽  
Activated Lymphocytes ◽  
Colon Carcinoma Cells

Heterogeneous lysability by interleukin-2 activated lymphocytes (LAK) and other immune effectors was observed in the human colon-carcinoma lines LoVo/Dx, LoVo/H and HT29. The tumor cells with high susceptibility to LAK (LoVo/Dx, HT29) expressed higher amounts of the adhesion molecules ICAMl, LFA3 and NCA/CEA than cells with low LAK sensitivity (LoVo/H). Monoclonal antibodies against these molecules caused a marked reduction of lysis by LAK of LoVo/Dx and HT29. A pool of these antibodies induced a nearly complete inhibition of the LAK lysis of both lines. Treatment of LoVo/Dx with differentiating agents (dimethylformamide and retinoic acid) led to a decreased expression of the adhesion molecules, including NCA, accompanied by increased resistance to LAK-mediated lysis. Moreover, the presence of CEA soluble antigen drastically inhibited the cytotoxic activity of LAK effectors against HT29 and LoVo/Dx cells, in a dose-dependent manner. These data indicate that sensitivity of colon-carcinoma cells to activated lymphocytes depends on the level of expression of adhesion molecules, including CEA and NCA. Given the role of CEA-related antigens in tumor/lymphocyte interaction, soluble CEA, frequently released by colon-carcinoma, may be involved in immunosuppressive effects induced in vivo by tumor cells.

The dual role of CD44 as a functional P-selectin ligand and fibrin receptor in colon carcinoma cell adhesion

2008 ◽  
Vol 294 (4) ◽  
pp. C907-C916 ◽  
Author(s):  
Christina S. Alves ◽  
Monica M. Burdick ◽  
Susan N. Thomas ◽  
Parag Pawar ◽  
Konstantinos Konstantopoulos
Keyword(s):  
Colon Carcinoma ◽  
Carcinoma Cell ◽  
Metastatic Potential ◽  
Carcinoma Cells ◽  
Fibrinogen Receptor ◽  
Colon Carcinoma Cells ◽  
Selectin Ligand ◽  
And Control ◽  
Kinetics Of

Selectins and fibrin(ogen) play key roles in the hematogenous dissemination of tumor cells, and especially of colon carcinomas. However, the fibrin(ogen) receptor(s) on colon carcinoma cells has yet to be defined along with its relative capacity to bind fibrinogen versus fibrin under flow. Moreover, the functional P-selectin ligand has yet to be validated using intact platelets rather than purified selectin substrates. Using human CD44-knockdown and control LS174T cells, we demonstrate the pivotal involvement of CD44 in the P-selectin-mediated binding to platelets in shear flow. Quantitative comparisons of the binding kinetics of LS174T versus P-selectin glycoprotein ligand-1 (PSGL-1)-expressing THP-1 cells to activated platelets reveal that the relative avidity of P-selectin-CD44 binding is more than sevenfold lower than that of P-selectin-PSGL-1 interaction. Using CD44-knockdown LS174T cells and microspheres coated with CD44 immunoprecipitated from control LS174T cells, and purified fibrin(ogen) as substrate, we provide the first direct evidence that CD44 also acts as the major fibrin, but not fibrinogen, receptor on LS174T colon carcinoma cells. Interestingly, binding of plasma fibrin to CD44 on the colon carcinoma cell surface interferes with the P-selectin-CD44 molecular interaction and diminishes platelet-LS174T heteroaggregation in the high shear regime. Cumulatively, our data offer a novel perspective on the apparent metastatic potential associated with CD44 overexpression on colon carcinoma cells and the critical roles of P-selectin and fibrin(ogen) in metastatic spread and provide a rational basis for the design of new therapeutic strategies to impede metastasis.

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