Disease relevance of TDGF1

• Eighty-two percent of breast carcinomas express Cr-1 whereas it is undetected in normal human breast tissue [1].
• All 18 patients in CR1 had one or more poor risk factors: age more than 18 (N = 17), initial leukocyte count greater than or equal to 20,000 (N = 11), Ph 1 chromosome (N = 2), delay in attaining CR more than 6 weeks (N = 8), or extramedullary disease (N = 1) [2].
• Cripto-1 overexpression leads to enhanced invasiveness and resistance to anoikis in human MCF-7 breast cancer cells [3].
• In addition, AR and CRIPTO immunoreactivity were found in 11 and in 26 out of 55 DCIS respectively [4].
• AR and CRIPTO immunoreactivity was also assessed in 55 human breast ductal carcinomas in situ (DCIS) [4].

High impact information on TDGF1

• To test whether CR ligands could be generated by the B cell receptor (BCR) itself, we generated similar mice carrying a mutated mIgM that was defective in C1q binding [5].
• Immunized CR knockout (KO) mice have lower antibody titers and smaller germinal centers (GCs), demonstrating the importance of CR signals for the humoral immune response [5].
• Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo [6].
• Thus, the enhanced phagocytosis and killing of opsonized bacteria by collagen-adherent monocytes appear to be by regulation of the function of membrane CR and FcR, without apparent enhancement of the respiratory burst [7].
• Adherence of monocytes to collagen gels activated C receptors (CR) types 1 and 3 for phagocytosis, and enhanced Fc receptor (FcR)-mediated phagocytosis [7].

Chemical compound and disease context of TDGF1

• Synergistic growth inhibition and induction of apoptosis by a novel mixed backbone antisense oligonucleotide targeting CRIPTO in combination with C225 anti-EGFR monoclonal antibody and 8-Cl-cAMP in human GEO colon cancer cells [8].
• Seventeen children with advanced myeloid malignancies (induction failure, relapse, myelodysplasia, secondary AML, or CR >1) received thiotepa 750 mg/m2 i.v., busulfan 12 mg/kg or 640 mg/m2 p.o., and cyclophosphamide 120 mg/kg i.v. as a preparative regimen for allogeneic or autologous hematopoietic stem cell (HSC) transplantation [9].
• Comamonas testosteroni 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase (3alpha-HSD/CR) is a key enzyme in the degradation of steroid compounds in soil, and may therefore play a significant role in the bioremediation of hormonally active substances in the environment [10].
• 3alpha-Hydroxysteroid dehydrogenase/carbonyl reductase (3alpha-HSD/CR) catalyses the oxidoreduction at carbon 3 of steroid hormones and is postulated to initiate the complete mineralisation of the steroid nucleus to CO(2) and H(2)O in Comamonas testosteroni [11].
• In the multivariate risk factor analysis of relapse, we found that the absence of chronic GVHD (P<.001), absence of herpes simplex virus infection after HSCT (P=.003), combination prophylaxis with methotrexate and cyclosporine (P=.01), and >6 weeks from the diagnosis to CR (P=.025) were independent risk factors for relapse after HSCT [12].

Biological context of TDGF1

• We propose a model in which Cripto has dual roles as a coreceptor as well as a coligand for Nodal and that this signaling interaction with Nodal is regulated by an unusual form of glycosylation [13].
• Infection of CID 9 cells with a Cr-1 antisense vector caused these cells to change in morphology, to grow slowly, to undergo apoptosis at a higher rate and to achieve lower saturation densities but the cells were still capable of differentiating [1].
• We concluded that Cr-1 is an autocrine growth factor for normal breast cells, that when over-expressed stimulates excessive cell proliferation at the expense of differentiation [1].
• Exogenous mouse Cr-1 expression from a retroviral vector caused CID 9 cells to grow at an increased rate and to increased cell densities compared to parental and control cells [1].
• Assignment of human teratocarcinoma derived growth factor (TDGF) sequences to chromosomes 2q37, 3q22, 6p25 and 19q13.1 [14].

Anatomical context of TDGF1

• Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells [15].
• We confirmed and extended findings that Cr-1 protein is expressed during the pregnancy and lactating stages of normal murine mammary glands but is barely detectable in glands from virgin animals and is undetectable in involuted glands [1].
• These data demonstrate that TGF alpha, AR, and CRIPTO expression are significantly increased in malignant mammary epithelium relative to normal epithelium [4].
• A truncated form of teratocarcinoma-derived growth factor-1 (cripto-1) mRNA expressed in human colon carcinoma cell lines and tumors [16].
• In contrast, cripto and AR mRNA were expressed in 60-70% of primary or metastatic human colorectal cancers but in only 2-7% of normal human colonic mucosa [17].

Associations of TDGF1 with chemical compounds

• We have found that the EGF-CFC family member human Cripto-1 (CR) is modified with fucose and through a combination of peptide mapping, mass spectrometry, and sequence analysis localized the site of attachment to Thr-88 [18].
• Finally, the apoptotic effect of LY294002 can be partially rescued by exogenous CR-1 [19].
• Histamine has been well tolerated, and 21/22 CR patients have treated themselves at home throughout the trial [20].
• However, the combination of taxol (5 x 10(-4) M) and NOC (2 x 10(-6) M) augmented M phi CR-mediated phagocytosis [21].
• In these studies Candida were found to mimic the human CR by binding erythrocytes coated with specific human C3 fragments [22].

Physical interactions of TDGF1

• Cripto has important roles during development and oncogenesis and binds nodal or related ligands and ALK4 to facilitate assembly of type I and type II receptor signaling complexes [23].
• Here we show that Cripto can form a complex with activin and ActRII/IIB [23].

Regulatory relationships of TDGF1

• In addition, Cripto blocked activin signaling when transfected into either HepG2 cells or 293T cells [23].
• Cripto-1 induces phosphatidylinositol 3'-kinase-dependent phosphorylation of AKT and glycogen synthase kinase 3beta in human cervical carcinoma cells [19].
• IL-10 almost completely reversed the IFN-gamma-induced inhibition of both Fc gamma R- and CR-mediated phagocytosis, without concomitant changes in membrane expression of phagocytic receptors [24].
• Consistent with its ability to block receptor assembly, Cripto suppressed TGF-beta signaling in multiple cell types and diminished the cytostatic effects of TGF-beta in mammary epithelial cells [25].
• Purified BPI completely inhibited CR up-regulation on neutrophils stimulated with both rough and smooth LPS chemotypes at 1.8 to 3.6 nM (100 to 200 ng/ml) [26].
• Transmembrane forms of CR-1 partially retained their ability to induce Nodal signaling only when type I receptor Activin-like kinase 4 was overexpressed [27].
• Shedding of CR-1 occurs at the GPI-anchorage site by the activity of GPI-phospholipase D (GPI-PLD), because CR-1 shedding was suppressed by siRNA knockdown of GPI-PLD and enhanced by overexpression of GPI-PLD [28].

Other interactions of TDGF1

• Using a luciferase reporter assay, we found that Cripto has activities consistent with its being a coreceptor for Nodal [13].
• A number of genes were down-regulated, which included LAR, ABL2, SKY, TDGF1 etc [29].
• In summary, our data suggest that human CR-1 may function as a survival factor through a PI3K-dependent signaling pathway involving AKT and GSK-3beta [19].
• We have also shown that under conditions in which Cripto facilitates nodal signaling, it antagonizes activin [23].
• They also expressed high levels of amphiregulin but did not express EGF and cripto [30].

Analytical, diagnostic and therapeutic context of TDGF1

• However, Cripto can also function as a secreted signaling factor in cell coculture assays, suggesting that it may also act as a coligand for Nodal [13].
• In transplantation studies, Cr-1 over-expression stimulated the growth and survival of mammary cells, but did not stimulate tumorigenesis in vivo [1].
• GCNF bound to a DR0 element of the CRIPTO-1 promoter in vitro, as shown by electrophoretic mobility shift assays, and in vivo, as demonstrated by chromatin immunoprecipitation [31].
• Interleukin 10, a mediator of UVB-induced immunosuppression, was unable to modulate CR expression in vitro [32].
• The majority of patients transplanted in CR1 (n=45) had high-risk features, including age above 30 years, white blood cell count at presentation exceeding 25000/microL, extramedullary disease, need for more than 4 weeks of induction chemotherapy to achieve CR, or high-risk chromosomal translocations [33].

References