LGR5 and CD133 as prognostic and predictive markers for fluoropyrimidine-based adjuvant chemotherapy in colorectal cancer

<p><b>Background:</b> Expression of leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5) gene is associated with a metastatic phenotype and poor prognosis in colorectal cancer (CRC). CD133 expression is a putative cancer stem cell marker and a proposed prognostic marker in CRC, whereas the predictive value of CD133 expression for effect of adjuvant chemotherapy in CRC is unclear.</p> <p><b>Material and methods:</b> For the study of LGR5 mRNA and CD133 expression, tissue microarrays from 409 primary CRC stage II and III tumors, where patients had been randomized to adjuvant chemotherapy or surgery only, were available. LGR5 mRNA and CD133 expression were assessed by in situ hybridization (ISH) and immunohistochemistry (IHC), respectively. LGR5 mRNA and CD133 expression as prognostic and predictive markers were evaluated by univariate and multivariate analyses.</p> <p><b>Results:</b> For all CRC patients, positive LGR5 mRNA and CD133 expression were associated with classic adenocarcinoma histology type (p = 0.001 and p = 0.014, respectively). Positive LGR5 mRNA expression was also associated with smaller tumor diameter for CRC stage II (p = 0.005), but not for CRC stage III (p = 0.054). For CRC stage II, lack of LGR5 mRNA expression was associated with longer time to recurrence (TTR) in Kaplan-Meier (p = 0.045) and in multivariate Cox analysis (HR 0.27, 95% CI 0.08–0.95, p = 0.041). For colon cancer stage III patients, lack of CD133 expression was associated with better effect of adjuvant chemotherapy (p = 0.016) in Kaplan-Meier univariate analysis, but the interaction between CD133 and adjuvant chemotherapy was not statistically significant in multivariate analysis (HR 0.59, 95% CI 0.18–1.89, p = 0.374).</p> <p><b>Conclusion:</b> LGR5 mRNA expression is a prognostic factor for CRC stage II patients, whereas the value of CD133 expression as prognostic and predictive biomarker is inconclusive.</p

Risk of ESRD among IgAN patients stratified by LBW, SGA or the combination of these, (gender-wise).

<p>Risk of ESRD among IgAN patients stratified by LBW, SGA or the combination of these, (gender-wise).</p

Cumulative Probability of ESRD in patients with IgAN according to whether or not the patient had LBW.

<p>Cumulative Probability of ESRD in patients with IgAN according to whether or not the patient had LBW.</p

Risk of ESRD among IgAN patients analysed at different percentile cut-offs for birth weight and birth weight for gestational age.

<p>Risk of ESRD among IgAN patients analysed at different percentile cut-offs for birth weight and birth weight for gestational age.</p

Cumulative Probability of ESRD in patients with IgAN according to whether or not the patient had SGA.

<p>Cumulative Probability of ESRD in patients with IgAN according to whether or not the patient had SGA.</p

Risk of ESRD according to whether the IgAN patients had LBW, SGA or preterm birth, separate analyses for male and female, Norway 1967–2013.

<p>Risk of ESRD according to whether the IgAN patients had LBW, SGA or preterm birth, separate analyses for male and female, Norway 1967–2013.</p

Image analysis of collagen in Picrosirius Red stained sections under polarised light.

<p>Collagen content is expressed as the percent of positive pixels to all pixels. * denotes P<0.05 compared to the contralateral kidney (CL). # denotes P<0.05 compared to OK in Mmp2+/+.</p

Morphological damage in the obstructed kidney (OK, 2B, D, F) compared to the contralateral kidney (CL, 2 A, C, E).

<p>All OK kidneys show tubular dilatation, flattened tubular epithelium with loss of brush border and reactive nuclear enlargement. Only Mmp2+/+ OK (2B) shows necrotic tubules (asterix) and many apoptotic cells (arrows). The morphology of the CL kidney is normal. (PAS stain).</p

Representative images of Picrosirius Red stained sections under polarised light from the obstructed kidney (OK, 3 B, D, F) compared to the contralateral kidney (CL, 3 A, C, E).

<p>There is a higher level of collagen in Mmp2+/+ OK (3 B) compared to OK in both Mmp2+/- and Mmp2-/- (3 D, F). Only minimal levels of collagen are detected in CL kidneys across all groups (3 A, C, E).</p

Representative images of Period Acid-Schiff (PAS) stained transversal sections showing increased morphological damage in the Mmp2+/+ obstructed kidney (OK, 1B) compared to the other groups (1 D, F).

<p>The Mmp2+/+ OK (1B) shows severe hydronephrosis and inflammation of the renal pelvis, while the Mmp2-/- OK (1F) and Mmp2+/- OK (1D) only display slight dilatation and minimal inflammation. The contralateral kidneys (CL, 1 A, C, E) do not differ from each other and show normal morphology.</p