The development of hepatocellular carcinomas (HCC) appears to be a multistep process that takes several decades in humans. However, the identities of specific gene alterations and their contribution to HCC pathogenesis remain poorly understood. We previously reported that Lkb1 +/--mice spontaneously develop multiple hepatic nodular foci (NdFc) followed by HCC, and that the conditional activation of b-catenin in Catnb lox(ex3) mouse livers alone does not cause tumor formation. We show here that the conditional activation of b-catenin accelerates HCC development in Catnb +/lox(ex3) Lkb1+/--compound mutant mice, affecting displastic hepatocytes in NdFc that suffered LOH at the Lkb1 locus. We further show that b-catnin activation provides HCC with a growth advantage as well as transplantability. These results suggest that the loss of Lkb1 contributes to the formation of dysplastic NdFc, and that Wnt signaling activation is involved in ensuing progression toward HCC. A combination of these sequential changes can be a practical model for a subset of human HCC. (Cancer Sci 2009; 100: 2046-2053 P eutz-Jeghers syndrome (PJS) is an autosomal dominant disease characterized by gastrointestinal hamartoma and mucocutaneous pigmentation as well as the increased risk of cancer.(1,2) The positional cloning studies on chromosome 19p13.3 identified mutations in LKB1 responsible for PJS. (3,4) LKB1 is a serine ⁄ threonine kinase that phosphorylates and activates 14 kinases, including AMP-activated protein kinase (AMPK) and microtubule-associated protein ⁄ microtubule affinity-regulating kinases (MARK).(5) Recent studies have revealed that LKB1 mediates energy-dependent suppression of the mammalian target of rapamycin (mTOR) pathway via AMPK, (6) and that LKB1 suppresses tubulin polymerization by activating MARK-microtubule-associated protein signaling. (7) We previously reported that Lkb1 + ⁄ ) mice develop gastrointestinal hamartomas that have similar histopathology to those in human PJS. (8) In addition, they developed multiple small nodular foci (NdFc) in the liver after 30 weeks of age, and HCC after 40 weeks of age.(9) NdFc consist of dysplastic and proliferative hepatocytes, suggesting that HCC in Lkb1 + ⁄ ) mice originate from these lesions.(9) LKB1 mutations have been identified not only in PJS patients but also in sporadic cancers.(10) Although the liver malignancy in PJS patients has been rarely reported, LKB1 is implicated in the pathogenesis of human HCC. A HCC cell line (BEL9204) and an immortalized hepatocyte line (TPH1) were found to bear homozygous deletions of the LKB1 gene, (11) and 1 of the 80 primary HCC examined had a point mutation in the LKB1 kinase domain.(12) These results suggest that LKB1 deficiency may underlie a subset of human HCC.Wnt signaling activation is a frequent change in HCC as well as in other cancers.(13) Upon activation, the adenomatous polyposis coli (APC)-axin-glycogen synthase kinase 3b (GSK3b) complex is unable to phosphorylate b-catenin, which results in the stabilization of b-catenin ...

We aimed to histologically observe portal venous gas (PVG)-causing intestinal pneumatosis (IP) and evaluate pathogenic mechanisms and therapeutic strategies, including decisions on whether emergency surgery should be performed. Autopsy was performed in two cases of nonocclusive mesenteric ischemia (NOMI). We directly histologically observed the pathogenic mechanisms of IP caused by gas-producing bacteria and IP considered to be caused by mechanical damage to the intestinal mucosa. IP can be classified hypothetically into the following types according to pathogenesis: (1) infection, (2) rupture (damage) of the intestinal mucosa + increased intestinal intraluminal pressure, and (3) mixed type. In cases of IP caused by gas-producing bacteria or IP associated with intestinal wall damage extending beyond the mucosa to the deep muscular layer, emergency surgery should be considered. However, it is highly possible that patients who test negative for infection with gas-producing bacteria whose intestinal wall damage remains only in the mucosa can be conservatively treated.

A patient with a potentially fatal condition as a result of esophago-pneumo-broncho fistula was successfully treated with the insertion of a self-expanded covered metallic stent. Severe regurgitation resulted in the removal of the stent 3 months after insertion. Stricture after removal of the stent required pneumatic balloon dilation. The use of a self-expanded covered metallic stent is effective for the treatment of spontaneous esophageal rupture; however, early removal of the stent is recommended.

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