Eradicating cancer cells: struggle with a chameleon

Eradication of cancer stem cells to abrogate tumor growth is a new treatment modality. However, like normal cells cancer cells show plasticity. Differentiated tumor stem cells can acquire stem cell properties when they gain access to the stem cell niche. This indicates that eradicating of stem cells (emptying of the niche) alone will not lead to eradication of the tumor. Treatment should be directed to cancer stem cells ànd more mature cancer cells

Clinical significance of circulating immune cells in left- and right-sided colon cancer

Background Left-sided and right-sided colon cancers (LCCs and RCCs, respectively) differ in their epidemiology, pathogenesis, genetic and epigenetic alterations, molecular pathways and prognosis. Notably, immune response gene expression profiles have been shown to differ between patients with LCC and patients with RCC. The immune system plays an important role in tumor immunosurveillance, and there is increasing evidence that peripheral blood immune cells have a profound influence on tumor prognosis. This study aimed to determine the clinical significance of circulating immune cells with respect to colon tumor locations. Methods Different types of circulating immune cells were separated and analysed based on their surface markers by flow cytometry. We compared the numbers of dendritic cells (DCs) and T cell subsets in the peripheral blood of 94 patients with RCC or LCC and analysed the proportions of these immune cells in relation to tumor stage, tumor differentiation and lymphatic metastasis. Results We show that at later tumor stages, patients with LCC had higher levels of circulating myeloid DCs (P = 0.049) and plasmacytoid DCs (P = 0.018) than patients with RCC. In poorly differentiated tumors, LCC patients had significantly higher amount of plasmacytoid DCs (P = 0.036), CD4+ memory T (Tm) cells (P = 0.012), CD4+ T cells (P = 0.028), Tm cells (P = 0.014), and regulatory T cells (P = 0.001) than RCC patients. The levels of circulating CD4+ T cells, Tm cells and CD4+ Tm cells were significantly elevated at later stages in patients with LCC or RCC, while these cells decreased in poorly differentiated tumors in patients with RCC. Moreover, CD4+ Tm cell and CD4+ T cell levels are significantly associated with lymph node metastasis in patients with LCC and RCC. Discussion Circulating immune cells were associated with tumor location, tumor stage and tumor differentiation, and can be used to predict lymphatic metastasis in patients with colon cancer. This variation in systemic immunity could contribute to the differential prognosis of patients with colon cancer

STK25-induced inhibition of aerobic glycolysis via GOLPH3-mTOR pathway suppresses cell proliferation in colorectal cancer

Abstract Background Serine/threonine protein kinase 25 (STK25) is critical in regulating whole-body glucose and insulin homeostasis and the accumulation of ectopic lipids. The Warburg effect, also known as aerobic glycolysis, is an essential metabolic characteristic of cancer cells. However, the effects of STK25 on aerobic glycolysis of cancer cells remain unexplored. The aim of this study is to investigate the role of STK25 in colorectal cancer (CRC) and to elucidate the underlying mechanisms. Methods The influences of STK25 on the cell proliferation were evaluated by MTT and colony formation assays. The roles of STK25 in aerobic glycolysis were determined by glucose uptake and lactate production assays. The interaction between STK25 and GOLPH3 was detected by co-immunoprecipitation, GST pull-down, and His-tag pull-down assays. Western blot was used to measure the expression of glycolytic genes, and the status of kinases in mTOR pathway. Moreover, a xenograft mouse model was used to investigate the effects of STK25 in vivo. The prognostic significance of STK25 was analyzed using public CRC datasets by a log-rank test. Results STK25 suppressed proliferation, glycolysis and glycolytic gene expression in CRC cells. STK25 interacted with GOLPH3 and mediated glycolysis through GOLPH3-regulated mTOR signaling. Consistent with these observations, silencing of STK25 promoted tumor growth and glycolytic gene expression in an in vivo xenograft mouse model. Moreover, high levels of STK25 correlated with favorable prognosis in patients with CRC. Conclusions Our results demonstrated that STK25 negatively regulates the proliferation and glycolysis via GOLPH3-dependent mTOR signaling. Accordingly, STK25 could be a potential therapeutic target for the treatment of CRC

Multi-region and single-cell sequencing reveal variable genomic heterogeneity in rectal cancer

Abstract Background Colorectal cancer is a heterogeneous group of malignancies with complex molecular subtypes. While colon cancer has been widely investigated, studies on rectal cancer are very limited. Here, we performed multi-region whole-exome sequencing and single-cell whole-genome sequencing to examine the genomic intratumor heterogeneity (ITH) of rectal tumors. Methods We sequenced nine tumor regions and 88 single cells from two rectal cancer patients with tumors of the same molecular classification and characterized their mutation profiles and somatic copy number alterations (SCNAs) at the multi-region and the single-cell levels. Results A variable extent of genomic heterogeneity was observed between the two patients, and the degree of ITH increased when analyzed on the single-cell level. We found that major SCNAs were early events in cancer development and inherited steadily. Single-cell sequencing revealed mutations and SCNAs which were hidden in bulk sequencing. In summary, we studied the ITH of rectal cancer at regional and single-cell resolution and demonstrated that variable heterogeneity existed in two patients. The mutational scenarios and SCNA profiles of two patients with treatment naïve from the same molecular subtype are quite different. Conclusions Our results suggest each tumor possesses its own architecture, which may result in different diagnosis, prognosis, and drug responses. Remarkable ITH exists in the two patients we have studied, providing a preliminary impression of ITH in rectal cancer

Expanding the BLUP alphabet for genomic prediction adaptable to the genetic architectures of complex traits

Improvement of statistical methods is crucial for realizing the potential of increasingly dense genetic markers. Bayesian methods treat all markers as random effects, exhibit an advantage on dense markers, and offer the flexibility of using different priors. In contrast, genomic best linear unbiased prediction (gBLUP) is superior in computing speed, but only superior in prediction accuracy for extremely complex traits. Currently, the existing variety in the BLUP method is insufficient for adapting to new sequencing technologies and traits with different genetic architectures. In this study, we found two ways to change the kinship derivation in the BLUP method that improve prediction accuracy while maintaining the computational advantage. First, using the settlement under progressively exclusive relationship (SUPER) algorithm, we substituted all available markers with estimated quantitative trait nucleotides (QTNs) to derive kinship. Second, we compressed individuals into groups based on kinship, and then used the groups as random effects instead of individuals. The two methods were named as SUPER BLUP (sBLUP) and compressed BLUP (cBLUP). Analyses on both simulated and real data demonstrated that these two methods offer flexibility for evaluating a variety of traits, covering a broadened realm of genetic architectures. For traits controlled by small numbers of genes, sBLUP outperforms Bayesian LASSO (least absolute shrinkage and selection operator). For traits with low heritability, cBLUP outperforms both gBLUP and Bayesian LASSO methods. We implemented these new BLUP alphabet series methods in an R package, Genome Association and Prediction Integrated Tool (GAPIT), available at http://zzlab.net/GAPIT

GATA2 rs2335052 Polymorphism Predicts the Survival of Patients with Colorectal Cancer

<div><p>Background</p><p>GATA binding protein 2 (GATA2) is a transcription factor that has essential roles in hematologic malignancies and progression of various solid tumors. Our previous studies suggested that high GATA2 expression is associated with recurrence of colorectal cancer (CRC). However, the influence of GATA2 single nucleotide polymorphisms (SNPs) on the survival of CRC remains unknown.</p><p>Methods</p><p>We genotyped GATA2 SNP rs2335052 using Sanger sequencing after PCR amplification, and determined GATA2 expression by immunohistochemistry in a cohort of 180 CRC patients. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to analyze the association between the GATA2 rs2335052 genotypes and the clinical outcome of CRC.</p><p>Results</p><p>We found that there was no significant correlation between the rs2335052 genotypes and the expression of GATA2. However, the Kaplan-Meier survival analysis suggested that the carriers of the A-allele of SNP rs2335052 were significantly associated with increased risk of recurrence and reduced disease-free survival (DFS), compared with those carrying the variant genotype of GG in rs2335052 (<i>P</i> = 0.021). Moreover, univariate and multivariate Cox regression analyses revealed that GATA2 SNP rs2335052 was an independent risk factor for the DFS of CRC patients.</p><p>Conclusion</p><p>Our results demonstrated that GATA2 SNP rs2335052 is an independent predictor for prognosis of CRC patients. This raised the possibility that SNP rs2335052 may serve as a potential indicator for predicting recurrence of CRC after curative colectomy.</p></div

Sequencing results of GATA2 rs2335052 genotypes.

<p>Sequencing results of GATA2 rs2335052 genotypes.</p

Univariate and multivariate analyses of GATA2 rs2335052 genotypes in CRC patients with respect to DFS.

<p><i>HR</i> hazard ratio, <i>CI</i> confidence interval, <i>P</i> values in bold were statistically significant.</p><p>Univariate and multivariate analyses of GATA2 rs2335052 genotypes in CRC patients with respect to DFS.</p

Clinicopathological features with respect to determined genotypes of included GATA2 SNP rs2335052.

<p>Differences in categorical study variables between genotypes were tested for statistical significance with the Chi-squared test. Tumors were classified according to the guidelines of the American Joint Committee on Cancer (AJCC) staging system.</p><p>Clinicopathological features with respect to determined genotypes of included GATA2 SNP rs2335052.</p