Sergei Tatishchev

Challenges to effective cancer control in China, India, and Russia

Cancer is one of the major non-communicable diseases posing a threat to world health. Unfortunately, improvements in socioeconomic conditions are usually associated with increased cancer incidence. In this Commission, we focus on China, India, and Russia, which share rapidly rising cancer incidence and have cancer mortality rates that are nearly twice as high as in the UK or the USA, vast geographies, growing economies, ageing populations, increasingly westernised lifestyles, relatively disenfranchised subpopulations, serious contamination of the environment, and uncontrolled cancer-causing communicable infections. We describe the overall state of health and cancer control in each country and additional specific issues for consideration: for China, access to care, contamination of the environment, and cancer fatalism and traditional medicine; for India, affordability of care, provision of adequate health personnel, and sociocultural barriers to cancer control; and for Russia, monitoring of the burden of cancer, societal attitudes towards cancer prevention, effects of inequitable treatment and access to medicine, and a need for improved international engagement.

Colorectal carcinoma: Pathologic aspects

Colorectal carcinoma is one of the most common cancers and one of the leading causes of cancer-related death in the United States. Pathologic examination of biopsy, polypectomy and resection specimens is crucial to appropriate patient managemnt, prognosis assessment and family counseling. Molecular testing plays an increasingly important role in the era of personalized medicine. This review article focuses on the histopathology and molecular pathology of colorectal carcinoma and its precursor lesions, with an emphasis on their clinical relevance.

Molecular mechanism of kNBC1–carbonic anhydrase II interaction in proximal tubule cells

We have recently shown that carbonic anhydrase II (CAII) binds in vitro to the C‐terminus of the electrogenic sodium bicarbonate cotransporter kNBC1 (kNBC1‐ct). In the present study we determined the molecular mechanisms for the interaction between the two proteins and whether kNBC1 and CAII form a transport metabolon in vivo wherein bicarbonate is transferred from CAII directly to the cotransporter. Various residues in the C‐terminus of kNBC1 were mutated and the effect of these mutations on both the magnitude of CAII binding and the function of kNBC1 expressed in mPCT cells was determined. Two clusters of acidic amino acids, L958DDV and D986NDD in the wild‐type kNBC1‐ct involved in CAII binding were identified. In both acidic clusters, the first aspartate residue played a more important role in CAII binding than others. A significant correlation between the magnitude of CAII binding and kNBC1‐mediated flux was shown. The results indicated that CAII activity enhances flux through the cotransporter when the enzyme is bound to kNBC1. These data are the first direct evidence that a complex of an electrogenic sodium bicarbonate cotransporter with CAII functions as a transport metabolon.

Critical amino acid residues involved in the electrogenic sodium-bicarbonate cotransporter kNBC1-mediated transport.

We have previously reported a topological model of the electrogenic Na+–HCO3− cotransporter (NBC1) in which the cotransporter spans the plasma membrane 10 times with N‐ and C‐termini localized intracellularly. An analysis of conserved amino acid residues among members of the SLC4 superfamily in both the transmembrane segments (TMs) and intracellular/extracellular loops (ILs/ELs) provided the basis for the mutagenesis approach taken in the present study to determine amino acids involved in NBC1‐mediated ion transport. Using large‐scale mutagenesis, acidic and basic amino acids putatively involved in ion transport mediated by the predominant variant of NBC1 expressed in the kidney (kNBC1) were mutated to neutral and/or oppositely charged amino acids. All mutant kNBC1 cotransporters were expressed in HEK‐293T cells and the Na+‐dependent base flux of the mutants was determined using intracellular pH measurements with 2′,7′‐bis‐(carboxyethyl)‐5(6)‐carboxyfluorescein (BCECF). Critical glutamate, aspartate, lysine, arginine and histidine residues in ILs/ELs and TMs were detected that were essential for kNBC1‐mediated Na+‐dependent base transport. In addition, critical phenylalanine, serine, tyrosine, threonine and alanine residues in TMs and ILs/ELs were detected. Furthermore, several amino acid residues in ILs/ELs and TMs were shown to be essential for membrane targeting. The data demonstrate asymmetry of distribution of kNBC1 charged amino acids involved in ion recognition in putative outward‐facing and inward‐facing conformations. A model summarizing key amino acid residues involved in kNBC1‐mediated ion transport is presented.

Stromal microRNA-21 levels predict response to 5-fluorouracil in patients with pancreatic cancer.

MicroRNA‐21 (miR‐21) is upregulated and inversely associated with survival in many cancer types, including pancreatic ductal adenocarcinoma (PDAC). We studied the predictive value of miR‐21 levels for gemcitabine or 5‐fluorouracil (5‐FU) response in tumor cells (TCs) or cancer associated fibroblasts (CAFs) in a cohort of PDAC patients from the RTOG 9704 trial.

Molecular mechanisms of electrogenic sodium bicarbonate cotransport: structural and equilibrium thermodynamic considerations.

The electrogenic Na+-HCO3− cotransporters play an essential role in regulating intracellular pH and extracellular acid-base homeostasis. Of the known members of the bicarbonate transporter superfamily (BTS), NBC1 and NBC4 proteins have been shown to be electrogenic. The electrogenic nature of these transporters results from the unequal coupling of anionic and cationic fluxes during each transport cycle. This unique property distinguishes NBC1 and NBC4 proteins from other sodium bicarbonate cotransporters and members of the bicarbonate transporter superfamily that are known to be electroneutral. Structure-function studies have played an essential role in revealing the basis for the modulation of the coupling ratio of NBC1 proteins. In addition, the recent transmembrane topographic analysis of pNBC1 has shed light on the potential structural determinants that are responsible for ion permeation through the cotransporter. The experimentally difficult problem of determining the nature of anionic species being transported by these proteins (HCO3− versus CO32−) is analyzed using a theoretical equilibrium thermodynamics approach. Finally, our current understanding of the molecular mechanisms responsible for the regulation of ion coupling and flux through electrogenic sodium bicarbonate cotransporters is reviewed in detail.

Whole exome sequencing of pediatric gastric adenocarcinoma reveals an atypical presentation of Li-Fraumeni syndrome.

Gastric adenocarcinoma is a rare diagnosis in childhood. A 14‐year‐old male patient presented with metastatic gastric adenocarcinoma, and a strong family history of colon cancer. Clinical sequencing of CDH1 and APC were negative. Whole exome sequencing was therefore applied to capture the majority of protein‐coding regions for the identification of single‐nucleotide variants, small insertion/deletions, and copy number abnormalities in the patients germline as well as primary tumor.

Genomic organization of the DCTN1-SLC4A5 locus encoding both NBC4 and p150Glued

In eukaryotes, it is rare for a single gene to encode two functionally unrelated proteins. p150Glued is a component of the dynactin heteromultimeric complex of proteins which is required for dynein-mediated vesicle and organelle transport by microtubules. NBC4 is an electrogenic sodium bicarbonate cotransporter, which regulates intracellular pH. Here we report that NBC4 and p150Glued are encoded by the same locus, DCTN1-SLC4A5. We have characterized the genomic organization of the human DCTN1-SLC4A5 locus which spans ∼230 kilobases on chromosome 2p13 and contains 66 exons. This information should allow the study of potential genomic alterations of DCTN1-SLC4A5 in patients with diseases mapping to this genomic region.

Helicobacter pylori infection and colorectal carcinoma: is there a causal association?

To the Editor, We would like to thank Dr. Kapetanakis and his colleagues for their interest in our article (1). We specifically appreciate the attention they brought to the importance of environmental factors, particularly Helicobacter pylori (H. pylori) infection, in the development of sporadic colorectal carcinoma (CRC). While the focus of our article was on the pathologic aspects (2), we would like to take this opportunity to extend our discussion to H. pylori as a potential etiopathogenetic factor in colorectal tumorigenesis. As mentioned by Dr. Kapetanakis and his colleagues, the development of sporadic CRC is associated with a variety of environmental factors including diet and lifestyle. Given that the colon harbors the largest number of microorganisms in the body, it is natural to assume that certain microbial species may play a role in colorectal tumorigenesis. The first reports connecting intestinal microflora with CRC were published back in the early 1950s. Streptococcus bovis septicemia was reported to be associated with carcinoma of the sigmoid colon (3). This association was subsequently supported by several publications (4-6). Animal studies have shown that S. bovis or its cell wall antigens promote the formation of hyperproliferative aberrant colonic crypts, enhance the expression of proliferation markers, and increase IL-8 production in the colonic mucosa (7). IL-8 is a proinflammatory cytokine that has been shown to promote the growth, angiogenesis and metastasis of colon cancer cells (8-11). Taken together, these observations suggest that S. bovis acts as a promoter of colorectal tumorigenesis. Later on in the mid-1970s, experiments with germ-free rats further showed that intestinal microflora played a modifying role in colorectal tumorigenesis. Germ-free rats developed much fewer colonic tumors compared to conventional rats when challenged with carcinogens (12,13). Since then, a number of commensal bacteria have been linked to CRC, including Escherichia coli, Enterococcus faecalis, Bacteroides spp. (B. fragilis, B. vulgatus, B. stercoris), Eubacterium limosum, and Clostridium septicum (14-22). Ever since the oncogenic properties of H. pylori were firmly established in the stomach, studies on its oncogenicity have extended to other parts of the gastrointestinal tract, particularly the colon (23). To date, the link between H. pylori infection and CRC remains inconclusive, with some reports showing an association (24-32) while others none (33-37). The results of two meta-analyses published in 2006 and 2008 both suggested a possible small increased risk of CRC in association with H. pylori infection (38,39). Several hypotheses have been proposed to explain the possible link between H. pylori infection and CRC. These include: (I) hypergastrinemia, (II) change in colorectal microflora, (III) toxin production, and (IV) chronic inflammation secondary to direct H. pylori colonization in the colon.

Acute eosinophilic appendicitis: a radiologic-pathologic correlation

Inflammation of the appendix is one of the most common conditions requiring emergent surgical intervention. Computed tomography commonly demonstrates a dilated appendix with adjacent inflammation. Traditionally, luminal obstruction of the appendix has been thought to be the primary etiology of appendicitis. However, current evidence suggests that etiology of appendicitis is multifactorial and can involve a number of different pathogenic pathways. Here we present a case of acute eosinophilic appendicitis with radiologic-pathologic correlation from a hypersensitivity reaction pathway. Acute eosinophilic appendicitis may represent an early precursor to conventional acute suppurative (phlegmonous) appendicitis, or a variant form of acute appendicitis.