Variation in Blood and Colorectal Epithelia’s Key Trace Elements Along with Expression of Mismatch Repair Proteins from Localized and Metastatic Colorectal Cancer Patients

Colorectal cancer (CRC) is an increasingly common medical issue affecting millions worldwide, and contribution of the body’s trace elements to CRC is arguable. The concentrations and buffered status of selenium, iron, copper, zinc, and phosphorus in blood and large intestinal tissues of CRC patients are, respectively, variable and vital for cell physiology. The aim of this study was to assess selenium, iron, copper, zinc, and phosphorus variations in blood and colorectal epithelia along with examining the expression of mismatch repair proteins in CRC patients with/without metastasis for potential diagnosis/therapy. Concentrations of selenium, iron, copper, zinc, and phosphorus in blood of healthy versus CRC patients and colorectal epithelia (adenocarcinomatous versus non-adenocarcinomatous/control) were measured in 40 CRC patients (55.87 ± 11.9 years old) with/without metastasis before surgery using ICP-OES. Mismatch repair (MMR) protein expression was analyzed through histopathological/immunohistochemistry assays, which was sparse in 5 CRC patient’s colorectal tissues (12%). Compared with healthy individuals, blood and colorectal tissue’s levels of phosphorus, copper, and iron were significantly higher in the CRC patients, and more pronounced in metastatic CRC patients; conversely, blood and colorectal tissue’s selenium levels were significantly lower in metastatic patients. Unlike blood zinc, cancerous colorectal tissue’s zinc concentration was significantly lower in CRC patients compared to healthy control cohorts. There was no significant difference on the measured elements in samples from CRC patients with MMR⁻ compared to CRC patients with MMR⁺. Receiver operating characteristic analysis revealed a correlation of blood iron, zinc, copper, and phosphorus to CRC, and inappropriately low levels of blood and colorectal selenium correlated with exacerbated metastasis. Altered levels of selenium, iron, copper, zinc, and phosphorus in vivo may impact the pathogenesis and detection of CRC, and their diagnostic/therapeutic potential in CRC would be revealing.

     

Cancer: Inappropriate Expression of Stem Cell Programs?

Cancer stem cells (CSCs) are a subpopulation of cancer cells that possess characteristics, including self-renewal, associated with normal stem cells. In this issue of Cell Stem Cell, Wong et al. (2008) define a core embryonic stem cell (ESC)-like gene expression program that may be important for CSC function in multiple epithelial cancers.     

Correction to: Variation in Blood and Colorectal Epithelia’s Key Trace Elements along with Expression of Mismatch Repair Proteins from Localized and Metastatic Colorectal Cancer Patients

Biological Trace Element Research - The original version of this article unfortunately contained a mistake. The name of “Ali Ghorbani Ranjbary” is now corrected in the author group of...     

Hypoxia-Inducible Factor-1α Polymorphisms and Risk of Cancer Metastasis: A Meta-Analysis

Background

HIF-1α is a major regulator in tumor progression and metastasis which responds to hypoxia. Many studies have demonstrated that hypoxia-inducible factor1-α (HIF-1α) polymorphisms are significantly associated with cancer metastasis, but the results are inconsistent. We conducted a comprehensive meta-analysis to estimate the associations between HIF-1α C1772 T polymorphism and cancer metastasis.

Methods

Comprehensive searches were conducted on PubMed and EMBASE database. Fifteen studies were included in the meta-analysis. We used the OR and 95%CI to assess the associations between HIF-1α C1772T polymorphism and cancer metastasis. Heterogeneity and publication bias were also assessed by Q test, I ², and funnel plot.

Results

Totally, fifteen studies including 1239 cases with metastasis-positive (M+) and 2711 cases with metastasis-negative (M−) were performed in this meta-analysis. The results showed that HIF-1a C1772T polymorphism was associated with the increased risk of cancer metastasis (T allele vs. C allele, OR  = 1.36, 95% CI  = 1.12–1.64; TT+ TC vs. CC, OR  = 1.39, 95% CI  = 1.13–1.71; TT vs. TC+ CC, OR  = 1.93, 95% CI  = 0.86–4.36). In the subgroup analyses, the significant associations remained significant among Asians, Caucasians and other cancers in the dominant model. Publication bias was not observed in the analysis.

Conclusions

Our results indicate that the HIF-1αC1772T polymorphism T allele may increase the risk of cancer metastasis, which might be a potential risk factor of cancer progress.     

Initiation of Colorectal Cancer: Where do the Two Hits Hit?

It is widely believed that stem cells are of special importance for colorectal cancer initiation. The earliest event being the inactivation of both alleles of the Adenomatous Polyposis Coli (APC) gene, it is thought that the stem cells are the most likely target for these two ?rst hits. Indeed, at the ?rst glance, short-lived differentiated cells cannot sustain a mutation longenough for the second hit to occur, because of the constantapoptosis/renewal process in epithelial tissues. Using a straightforward calculation, we show that this intuitive argument is incorrect.Our model basedon the conventional view of colon cryptarchitecture, suggests thatat least one ofthe two hits mayoccur in the migrating compartment. We suggest that a possible role of differentiating cells in cancer initiation cannot be discarded simply based on the fact that theyare short–lived. More evidence is neededto understandthe cellular origins of cancer and to identify whether or not a double hit in a daughter cell can be “immortalizing”. In this study we discuss several scenarios and propose some experiments which can shed light on these questions.     

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

WNT signaling was discovered in tumor models and has been recognized as a regulator of cancer development and progression for over 3 decades. Recent work has highlighted a critical role for WNT signaling in the metabolic homeostasis of mammals, where its misregulation has been heavily implicated in diabetes. While the majority of WNT metabolism research has focused on nontransformed tissues, the role of WNT in cancer metabolism remains underinvestigated. Cancer is also a metabolic disease where oncogenic signaling pathways regulate energy production and macromolecular synthesis to fuel rapidly proliferating tumors. This review highlights the emerging evidence for WNT signaling in the reprogramming of cancer cell metabolism and examines the role of these signaling pathways as mediators of tumor bioenergetics.     

Cancer: A matter of life cycle?

In the last decade, the concept of "cancer stem cells" has emerged, recognised by the fact that only a small fraction of tumour cells appears to retain the stem cell properties of self-renewal and unlimited proliferation. At the same time, it is well known that cancer is an age-related disease developing at the limit of proliferating cell senescence. The apparent need to link senescence and the capacity for self-renewal has lead some authors to suggest that cancers develop from amongst senescing stem cells. However, an alternative solution has recently been proffered by Sundaram M, Guernsey DL, Rajaraman MM, Rajaraman R [Neosis: a novel type of cell division in cancer. Cancer Biol Ther 2004;3:207-18], who suggest that stemness may be a transient, cyclic property afforded by de-polyploidisation of senescing cells which have undergone polyploidisation. In this mini-review, we attempt to reconcile both of these views by the idea that cycling polyploidy intermitting senescence and rejuvenation may be features of a life cycle analogous to the life cycles of certain unicellular organisms. Furthermore, we suggest that mitotic catastrophe may represent a mechanism through which the cell can switch from the usual mitotic cell-cycle to this evolutionarily conserved life cycle. Intriguingly, some most recent data suggest that cell senescence may be reversible and that stem cells are tolerant to polyploidy caused by genotoxic stress.     

A Highlights from MBoC Selection: Rab5 Mediates Caspase-8–promoted Cell Motility and Metastasis

Caspase-8 is a key apical sensory protein that governs cell responses to environmental cues, alternatively promoting apoptosis, proliferation, and cell migration. The proteins responsible for integration of these pathways, however, have remained elusive. Here, we reveal that Rab5 regulates caspase-8–dependent signaling from integrins. Integrin ligation leads to Rab5 activation, association with integrins, and activation of Rac, in a caspase-8–dependent manner. Rab5 activation promotes colocalization and coprecipitation of integrins with caspase-8, concomitant with Rab5 recruitment to integrin-rich regions such as focal adhesions and membrane ruffles. Moreover, caspase-8 expression promotes Rab5-mediated internalization and the recycling of β1 integrins, increasing cell migration independently of caspase catalytic activity. Conversely, Rab5 knockdown prevented caspase-8–mediated integrin signaling for Rac activation, cell migration, and apoptotic signaling, respectively. Similarly, Rab5 was critical for caspase-8–driven cell migration in vivo, because knockdown of Rab5 compromised the ability of caspase-8 to promote metastasis under nonapoptotic conditions. These studies identify Rab5 as a key integrator of caspase-8–mediated signal transduction downstream of integrins, regulating cell survival and migration in vivo and in vitro.     

Autophagy and Self-Preservation: A Step Ahead from Cell Plasticity?

Silencing the SPINK-related gene Kazal1 in hydra gland cells induces an excessive autophagy of both gland and digestive cells, leading to animal death. Moreover, during regeneration, autophagosomes are immediately detected in regenerating tips, where Kazal1 expression is lowered. When Kazal1 is completely silenced, hydra no longer survive the amputation stress (Chera S, de Rosa R, Miljkovic-Licina M, Dobretz K, Ghila L, Kaloulis K, and Galliot B. Silencing of the hydra serine protease inhibitor Kazal1 gene mimics the human Spink1 pancreatic phenotype. J Cell Sci 2006; 119:846-57). These results highlight the essential digestive and cytoprotective functions played by Kazal1 in hydra. In mammals, autophagy of exocrine pancreatic cells is also induced upon SPINK1/Spink3 inactivation, whereas SPINK3 is activated in injured pancreatic cells. Hence SPINKs, by preventing an excessive autophagy, appear to act as key players of the stress-induced self-preservation program. In hydra, this program is a prerequisite to the early cellular transition, whereby digestive cells of the regenerating tips transform into a head-organizer center. Enhancing the self-preservation program in injured tissues might therefore be the condition for unmasking their potential cell and/or developmental plasticity.

Addendum to:

Silencing of the Hydra Serine Protease Inhibitor Kazal1 Gene Mimics the HumanSpink1 Pancreatic Phenotype

S. Chera, R. de Rosa, M. Miljkovic-Licina, K. Dobretz, L. Ghila, K. Kaloulis and B. Galliot

J Cell Sci 2006; 119:846-57     

Asymmetric Segregation of Aged Spindle Pole Bodies During Cell Division: Mechanisms and Relevance Beyond Budding Yeast?

Asymmetric cell division generates cell diversity and contributes to cellular aging and rejuvenation. Here, we review the molecular mechanisms enabling budding yeast to recognize spindle pole bodies (SPB, centrosome equivalent) based on their age, and guide their non‐random mitotic segregation: SPB inheritance requires the distinction of old from new SPBs and is regulated by the SPB‐inheritance network (SPIN) and the mitotic exit network (MEN). The SPIN marks the pre‐existing SPB as old and the MEN recognizes these marks translating them into spindle orientation. We next revisit other molecules and structures that partition depending on their age rather than their abundance at mitosis as, for example, DNA, centrosomes, mitochondria, and histones in yeast and other systems. The recurrence of this differential behavior suggests a functional significance for numerous cell types, which we then discuss. We conclude that non‐random segregation may facilitate asymmetric cell fate determination and thereby indirectly aging and rejuvenation. Also see the video abstract here: https://youtu.be/1sQ4rAomnWY .     

HIF-1α Promotes Epithelial-Mesenchymal Transition and Metastasis through Direct Regulation of ZEB1 in Colorectal Cancer

It is well recognized that hypoxia-inducible factor 1 alpha (HIF-1α) is involved in cancer metastasis, chemotherapy and poor prognosis. We previously found that deferoxamine, a hypoxia-mimetic agent, induces epithelial-mesenchymal transition (EMT) in colorectal cancer. Therefore, here we explored a new molecular mechanism for HIF-1α contributing to EMT and cancer metastasis through binding to ZEB1. In this study, we showed that overexpression of HIF-1α with adenovirus infection promoted EMT, cell invasion and migration in vitro and in vivo. On a molecular level, HIF-1α directly binding to the proximal promoter of ZEB1 via hypoxia response element (HRE) sites thus increasing the transactivity and expression of ZEB1. In addition, inhibition of ZEB1 was able to abrogate the HIF-1α-induced EMT and cell invasion. HIF-1α expression was highly correlated with the expression of ZEB1 in normal colorectal epithelium, primary and metastatic CRC tissues. Interestingly, both HIF-1α and ZEB1 were positively associated with Vimentin, an important mesenchymal marker of EMT, whereas negatively associated with E-cadherin expression. These findings suggest that HIF-1α enhances EMT and cancer metastasis by binding to ZEB1 promoter in CRC. HIF-1α and ZEB1 are both widely considered as tumor-initiating factors, but our results demonstrate that ZEB1 is a direct downstream of HIF-1α, suggesting a novel molecular mechanism for HIF-1α-inducing EMT and cancer metastasis.     

Cancer Cell:癌症治疗新思路

<正>近年来,热门的癌症化个体化治疗方案往往聚焦于,与不同类型的癌症相关联的,特异性的基因突变。不同于以往的癌症作用靶点,近日,来自Saint Louis大学的研究人员们首次发现,一种靶向Warburg效应的药物,可以从根源上阻断癌症的能量来源,从而使癌症细胞停止生长。这项研究结果最近发表于Cancer Cell杂志上。我们知道,所有的生物均有利用能量的能力,即代谢。癌症细胞大大地加快了代谢过程,使突变的细胞疯狂地生长。早在20世纪初,科学家们