Progastrin production transitions from Bmi1+/Prox1+ to Lgr5high cells during early intestinal tumorigenesis.

Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear. Here, we used a combination of immunostaining, RNAscope labelling and retrospective analysis of single cell RNAseq results to demonstrate that progastrin is produced within intestinal crypts by a subset of Bmi1+/Prox1+/LGR5low endocrine cells, previously shown to act as replacement stem cells in case of mucosal injury. In contrast, our findings indicate that intestinal stem cells, specified by expression of the Wnt signaling target LGR5, become the main source of progastrin production in early mouse and human intestinal adenomas. Collectively our results suggest that the previously identified feed-forward mechanisms between progastrin and Wnt signaling is a hallmark of early neoplastic transformation in mouse and human colonic adenomas.

The COOH-terminal Src kinase Csk is a tumor antigen in human carcinoma.

The cytoplasmic tyrosine kinase cSrc is involved in the regulation of many important cellular functions including cell growth and transformation, and its activity is down-regulated by phosphorylation of the Tyr530 residue by the COOH-terminal Src tyrosine kinase, Csk. Because cSrc was previously found overexpressed, activated, and in some cases mutated in carcinoma, we investigated whether it could act as a tumor antigen. We show that whereas no autoantibodies were found against cSrc or its relative Fyn, up to 20% of patients with carcinoma had high-affinity autoantibodies against Csk. Immunity mainly resulted from a secondary response, as indicated by the presence of IgG1 in the sera. Antibodies were linked to the cancer because they were not detected in healthy subjects nor in patients with unrelated diseases, and their levels decreased in the sera of patients after surgical resection. Furthermore, they behaved as early markers of epithelial transformation because they were present in sera of patients with early-stage tumors and precancerous lesions such as colorectal polyps and in sera of patients that were scored negative for other cancer serological markers (CEA, CA15-3, CA19-9, p53 antibodies). Finally the presence of these antibodies was attributed, at least in part, to a substantial elevation of Csk protein levels in the corresponding tumors. However a strong increase in Src activity was also observed in these tissues, which suggested that Csk cannot regulate Src-like activity in carcinoma. Taken together, these data demonstrate that Csk acts as an autoantigen, and the detection of anti-Csk antibodies may have potential diagnostic usefulness in the early detection and postoperative follow-up of patients with carcinoma.

[Multivisceral resections of extracolorectal lesions in familial adenomatous polyposis]. / Exérèses multiviscérales dans les polyposes familiales adénomateuses. A propos de neuf observations.

AIMS: 1/ To report our experience with multivisceral resections in familial adenomatous polyposis (FAP) for extracolorectal lesions in a cohort of nine patients. 2/ Discuss the long term results of an agressive surgery. PATIENTS AND METHODS: Nine patients (7 males and 2 females) were operated at the University Hospital of Nimes (N=4) and Nantes (N=5). The median age at the first operation was 29 years (range 18-43). A genetic study was performed in six patients and confirmed the mutation on APC gene (exon 11, 13 and 15). All the patients were operated through a classic laparotomy. RESULTS: All patients have underwent a mean of three operations (range 2-5). Eight patients have had initially a total colectomy and 4 underwent subsequent proctectomy. Seven patients had pancreaticoduodenectomy for extensive duodenal adenomas and/or carcinoma. Three had one or multiple small bowel resections for development of carcinoma and one had partial gastric resection for large adenovillous tumor. The median follow up was 25 years (range 15-37) since the first operation. Three patients were died: one of gastric cancer with hepatic metastases, one of peritoneal carcinosis after ileal resection and one of astrocytoma. CONCLUSION: With regard to these nine observations, the authors underline the possibility of multivisceral resection in FAP. Despite a major digestive mutilation, it permits a long survival with acceptable quality of life. The prognosis depends on the aggressiveness of the duodenal or jejunoileal lesions more than of the colorectal tumors if found at the first resection.

[Highly elevated alphafetoprotein and hepatic cirrhosis. It is not always hepatocarcinoma]. / Alpha-foetoprotéine très élevée et cirrhose hépatique. Ce n'est pas toujours un hépatocarcinome.

BACKGROUND: Alphafetoprotein assay contributes considerably to the diagnosis of hepatocarcinoma in patients with hepatic cirrhosis. We report the case of a cirrhotic patient whose elevated alphafetoprotein level was not associated with liver disease. CASE REPORT: Alphafetoprotein level was followed in a 64-year-old man with hepatic cirrhosis. A rise from 415 to 7690 ng/ml between June and November 1997 led to the discovery of adenocarcinoma of the cardia with liver metastasis. This extrahepatic adenocarcinoma was probably the cause of inappropriate secretion of alphafetoprotein. DISCUSSION: Primary liver tumors are obviously not the only source of elevated alphafetoprotein levels. High levels can also be observed in certain, notably digestive tract and embryonary, cancers. Gastric hepatoid adenocarcinoma is a recently described histological entity first described in 1970. Typically, there is an inappropriate secretion of alphafetoprotein due to a secondary liver tumor.

[Percutaneous hepatic puncture biopsy in ambulatory care. 231 patients]. / Ponction biopsie hépatique transpariétale en aveugle et en ambulatoire. 231 patients.

OBJECTIVES: The aim of this study was to verify that percutaneous liver biopsy does not require prolonged hospitalization over 24 hours and can be performed in a day care clinic without increased morbidity. PATIENTS AND METHODS: Two hundred thirty-one outpatients underwent percutaneous liver biopsies in a day care clinic from November 1, 1994 to June 30, 1996. There were 136 men and 95 women, mean age 39.5 years, age range 16-72 years. Liver biopsy was performed as part of the work-up for hepatitis C in 183 patients. The biopsy was a repeat procedure in 43 patients. RESULTS: The procedure was uneventful in 230 patients. Hospitalization for 24 hours was required in one patient with a biliodigestive anastomosis who developed chills and fever due to Eschericia coli bacteremia. Two procedures were unsuccessful. CONCLUSION: This series confirms that when performed in compliance with standard rules for strictly controlled indications, morbidity after percutaneous liver biopsy is not greater in an outpatient than a classical inpatient setting.

[Laparoscopic colorectal resection for deep pelvic endometriosis: Evaluation of post-operative outcome]. / Résections rectosigmoïdiennes cœlioscopiques pour endométriose digestive : résultats chirurgicaux et fonctionnels.

OBJECTIVES: Evaluation of mid-term functional results and the quality of life after laparoscopic colorectal resection. PATIENTS AND METHODS: Twenty-three consecutive patients were included in a retrospective monocentric study. Postoperative functional outcomes and quality of life were analyzed. RESULTS: The median follow-up after colorectal resection was of 24±15.7 months (6-72). Major complications occurred in three cases (12,9%) including one anastomotic stenosis, one digestive and one bladder fistula. A significant improvement in pelvic pain symptoms was observed. De novo constipation and pain on defecation occurred in respectively 23% and 42% of the cases. Transient de novo dysuria occurred in 18% of the cases. The quality of life has been significantly improved. CONCLUSION: Laparoscopic colorectal resection is associated with unfavourable postoperative digestive and urological outcomes, such as bladder and rectal dysfunction. Radical treatment should be limited to selected patients.

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization.

The nonreceptor tyrosine kinases of the Src family (SFK) are frequently deregulated in human colorectal cancer (CRC), and they have been implicated in tumour growth and metastasis. How SFK are activated in this cancer has not been clearly established. Here, we show that the SFK-dependent invasion is induced by inactivation of the negative regulator C-terminal Src kinase, Csk. While the level of Csk was inconsistent with SFK activity in colon cancer cells, its membrane translocation, needed for efficient regulation of membrane-localized SFK activity, was impaired. Accordingly, Csk downregulation did not affect SFK oncogenic activity in these cells, whereas expression of a membrane-localized form of this kinase affected their invasive activity. Downregulation of the transmembrane and rafts-localized Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomain (PAG), was instrumental for the cytoplasmic accumulation of Csk. Re-expression of PAG in cells from late-stage CRC inhibited SFK invasive activity in a Csk-dependent manner. Conversely, inactivation of its residual expression in early-stage CRC cells promoted SFK invasive activity. Finally, this mechanism was specific to CRC as Csk coupling to SFK was readily detected in breast cancer cells. Therefore, Csk mis-localization defines a novel mechanism for SFK oncogenic activation in CRC cells.

p53 and follow-up of colorectal adenocarcinomas.

Circulating p53 antibodies (ELISA method), p53 genetic alterations (SSCP), and protein overexpression (immunohistochemistry) were studied in 41 patients with colorectal adenocarcinomas and 10 control patients. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA 19-9) were evaluated in parallel. Ten patients with p53 antibodies and p53 overexpression were selected. Tumor DNA extracts from these 10 patients were analyzed by SSCP. Of all 41 patients, 10 (24%) showed significant levels of p53 antibodies, and p53 accumulation was detected in 20 (48%) patients. In six patients, p53 antibody concentrations decreased rapidly after surgery; in two patients, these levels returned to normal values. Of the 10 selected tumors, eight revealed TP53 gene mutations. Only two patients with high values of both CEA and CA 19-9 developed p53 antibodies. In conclusion, beside classical tumor markers, circulating p53 antibodies may be considered as additional markers for the management of patients with colorectal adenocarcinomas.