PubMed · 12432125
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Michael N Brant-Zawadzki. Screening CT: rationale.. https://doi.org/10.1148/rg.226025059
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PURPOSE: Current estimates of the proportion of cancer patients who will require RT are based almost entirely on expert opinion. The objective of this study was to estimate the proportion of incident cases of colorectal cancer that should receive RT using an evidence-based approach. METHODS AND MATERIALS: A systematic review of the literature was undertaken to identify indications for RT for colorectal cancer, and to ascertain the level of evidence that supported each indication. An epidemiologic approach was then used to estimate the incidence of each indication for RT in a typical North American population of colorectal cancer patients. The effect of sampling error on the estimated appropriate rate of RT was calculated mathematically, and the effect of systematic error was estimated by sensitivity analysis. RESULTS: It was estimated that 23.7% +/- 1.0% of colorectal cancer cases develop one or more indications for RT at some point in the course of the illness: 20.9% +/- 1.1% as part of their initial treatment, and 2.8% +/- 0.5% later for recurrence or progression. We estimated that 7.1% +/- 0.8% of colon carcinoma patients will require RT at some point in the course of the illness: 4.0% +/- 0.7% as part of their initial treatment, and 3.1% +/- 0.4% later for recurrence or progression. We estimated that 72.3% +/- 1.0% of rectal carcinoma patients will require RT at some point in the course of the illness: 69.6% +/- 0.9% as part of their initial treatment and 2.7% +/- 0.2% later for recurrence or progression. CONCLUSIONS: This method provides a rational starting point for the long-term planning of radiation services, and for the audit of access to RT at the population level. By completing such evaluations in the major cancer sites, it will be possible to estimate the appropriate RT treatment rate for the cancer population as a whole.
Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and beta1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/beta1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with beta1 integrin in mock-transfected cells. Disruption of uPAR-beta1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR-integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer.
Overexpression of cyclooxygenase-2 (COX-2) has been observed in human colorectal cancer. COX-2 expression in human tumors can be induced by growth factors, cytokines, oncogenes, and other factors. The mechanisms regulating COX-2 expression in human colon cancer have not been completely elucidated. We hypothesized that the proinflammatory cytokine interleukin-1 beta (IL-1 beta) mediates COX-2 expression in HT-29 human colon cancer cells. Treatment of HT-29 cells with IL-1 beta induced expression of COX-2 mRNA and protein in a time- and dose-dependent manner. Inhibitors of the extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase, P38 mitogen-activated protein kinase, and nuclear factor-kappa B (NF-kappa B) signaling pathways blocked the ability of IL-1 beta to induce COX-2 mRNA. In contrast, Wortmannin, a phosphoinositide 3-kinase inhibitor upstream of protein kinase B/Akt, led to a slight increase in COX-2 mRNA expression after IL-1 beta treatment. Electrophoretic mobility shift assay on nuclear extracts demonstrated that IL-1 beta induced NF-kappa B DNA binding activity in HT-29 cells, and the activated NF-kappa B complex was eliminated after treatment with an inhibitor of NF-kappa B. Supershift assay indicated that the two NF-kappa B subunits, p65 and p50, were involved in activation of NF-kappa B complex by IL-1 beta stimulation. The stability of COX-2 mRNA was not altered by IL-1 beta treatment. These data demonstrate that IL-1 beta induces COX-2 expression in HT-29 cells through multiple signaling pathways and NF-kappa B.