Gene signatures derived from cancer stem cells (CSCs) predict tumor recurrence for many forms of cancer. Here, we derived a gene signature for colorectal CSCs defined by high Wnt signaling activity, ...which in agreement with previous observations predicts poor prognosis. Surprisingly, however, we found that elevated expression of Wnt targets was actually associated with good prognosis, while patient tumors with low expression of Wnt target genes segregated with immature stem cell signatures. We discovered that several Wnt target genes, including
ASCL2 and
LGR5, become silenced by CpG island methylation during progression of tumorigenesis, and that their re-expression was associated with reduced tumor growth. Taken together, our data show that promoter methylation of Wnt target genes is a strong predictor for recurrence of colorectal cancer, and suggest that CSC gene signatures, rather than reflecting CSC numbers, may reflect differentiation status of the malignant tissue.
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► Wnt target genes, including stem cell markers, inversely correlate with prognosis ► Progression of CRC is associated with methylation of Wnt target genes ► Adherence to CSC signatures reflects an immature clonal trait, not CSC numbers ► Wnt target methylation is a strong prognostic marker
The levels of TNF, IL-1 and IL-6 in circulating blood of female WAG/Rij rats were assessed both after total-body irradiation (TBI) and localized irradiation of the right hind leg. The results show ...that enhanced levels of IL-1 in the circulation reflect a stress situation presumably resulting from handling and halothane anesthesia of the animal. Neither localized irradiation nor TBI resulted in further enhanced levels of IL-1. Both TBI and localized irradiation, lead to a small but significant increase in IL-6 levels in serum from circulating blood. After TBI this increase dissipated rapidly, 24 h after TBI increased levels are not found. After localized irradiation IL-6 levels remain elevated for a longer period. Still two weeks after irradiation, the longest time investigated, increased levels were observed. We did not observe increased TNF levels after localized irradiation or after TBI.
APRIL (A proliferation-inducing ligand) is a TNF family member that binds two TNF receptor family members, TACI and BCMA. It shares these receptors with the closely related TNF family member, B-cell ...activating factor (BAFF). Contrary to BAFF, APRIL binds heparan sulfate proteoglycans (HSPGs), which regulates cross-linking of APRIL and efficient signaling. APRIL was originally identified as a growth promoter of solid tumors, and more recent evidence defines APRIL also as an important survival factor in several human B-cell malignancies, such as chronic lymphocytic leukemia (CLL). To target APRIL therapeutically, we developed two anti–human APRIL antibodies (hAPRIL.01A and hAPRIL.03A) that block APRIL binding to BCMA and TACI. Their antagonistic properties are unique when compared with a series of commercially available monoclonal anti–human APRIL antibodies as they prevent in vitro proliferation and IgA production of APRIL-reactive B cells. In addition, they effectively impair the CLL-like phenotype of aging APRIL transgenic mice and, more importantly, block APRIL binding to human B-cell lymphomas and prevent the survival effect induced by APRIL. We therefore conclude that these antibodies have potential for further development as therapeutics to target APRIL-dependent survival in B-cell malignancies.
Purpose
: Investigation of the effects of hyperthermia on the radiation response of rat lumbosacral spinal cord with respect to: (a) incidence of paralysis, (b) latency, (c) histopathology, and (d) ...tumor induction.
Methods and Materials
: Rat lumbosacral spinal cord with the cauda equina was single-dose irradiated with 15 to 32 Gy of x-rays. Hypethermia for 30 min at a spinal cord temperature of 41.1, 42.3, and 42.6 ± 0.4°C was appplied 5 to 10 min after irradiation by means of a 434 MHz microwave applicator. Animals were observed for 21 months whiel recording myelopathy and development of tumors.
Results
: The latent period for hind leg paralysis decreased with increasing radiation dose from 359 ± 31 days (
n = 9) after 20 Gy to 200 ± 4 days (
n = 5) after 32 Gy. Hyeprthermia enhanced the radiation response of the lumbosacral spinal cord as evidenced by shortening of the latent period for paralysis and a decrease in the biological effective dose. After 20 Gy followed by 30 min 41.1°C, latency was diminished to 214 ± 16 days (
n = 7,
p < 0.001 vs. 20 Gy alone). The ED
50 was 21.1 Gy, which was diminished to values between 15 and 17 Gy if radiation was followed by hyperthermia, giving a thermal enhancement ratio between 1.24 and 1.32. Histopathological examination of the spinal cord after combined treatment of x-rays and hyperthermia showed necrosis of nerve roots.Irradiation with 16, 20, 24, and 28 Gy (
n = 77) alone led to tumor induction in 17 ± 8% of the animals (pooled data). If followed by hyperthermia (
n = 96), it was increased to 33 ± 12% (
p < 0.01). Most tumors induced by radiation and hyperthermia were sarcomas.
Conclusion
: First, the radiation response of rat lumbosacral spinal cord was enhanced by theat. Second, latency for paralysis was shortened in the lower dose range. Third, no difference in pathology between x-rays alone or in combination with hyperthermia. Fourth, hyperthermia did increase radiation carcinogenesis.
Sensitization by bromodeoxyuridine (BrdUrd) and hyperthermia (HT) on cell reproductive death induced by ionizing radiation was analyzed using the linear-quadratic S(D)/S(0)=exp{-( αD+βD2 )} model. ...Plateau-phase human lung tumor cells (SW-1573) and human colorectal carcinonoma cells (RKO) were treated with BrdUrd, radiation and HT. LQ-analysis was performed at iso-incubation dose and at iso-incorporation level of BrdUrd, and at iso-HT doses and iso-survival levels after HT. Clonogenic assays were performed 24 h after treatment to allow repair of potentially lethal damage (PLD). In SW cells BrdUrd, HT or the combination significantly increased the α-parameter (factor 2.0-5.7), without altering the β-parameter. In RKO cells sensitization with BrdUrd increased both α (factor 1.4) and β (factor 1.3) while HT only influenced β (factor 2.1-4.0). The combination did not further increase the α and β. The results indicate that BrdUrd has its main effect on the parameter α, dominant at clinically relevant radiation doses but that HT can affect both α and β. The addition of BrdUrd and HT provides a method to enhance the efficacy of radiotherapy.
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