Operative injury accelerates tumor growth by inducing mobilization and recruitment of bone marrow-derived stem cells.

BACKGROUND: Although operative injury is thought generally to worsen the prognosis of cancer patients, the relevant mechanisms are not yet understood fully. We tested the hypothesis that operative injury induces mobilization and recruitment of bone marrow stem cells, thereby enhancing angiogenesis and accelerating tumor growth. METHODS: Mice were subjected to an open gastrotomy, and naïve mice were used as controls. The mobilization of bone marrow stem cells was monitored after operation. Using an established tumor model in green fluorescent protein (GFP)(+) bone marrow-transplanted chimera mice, we investigated further whether the mobilized stem cells affected tumor growth. RESULTS: Compared with the control, gastrotomy increased the populations of CD34(+) cells (6.9 ± 4.5 % vs 3.3 ± 0.4%, P < .05) and CD34(+)/Flk-1(+) cells (0.08 ± 0.02% vs 0.05 ± 0.01%, P < .05) in peripheral blood 12 h after operation. Twelve days after operation, the tumor volume almost doubled in mice after gastrotomy compared with control (580 ± 106 mm(3) vs 299 ± 162 mm(3), P < .05). A histologic analysis of tumor tissue revealed that the microvessel density and number of proliferating cells were significantly greater, but those of apoptotic cells were significantly less, in mice after gastrotomy as compared with control. Furthermore, the number of GFP(+) cells found in tumor tissue was significantly greater in mice that underwent gastrotomy than in controls. Some of the stained GFP(+) cells were positive for CD34 and had been incorporated into microvessels. Administration of AMD3100, which is an antagonist of stromal-cell-derived factor (SDF)-1/CXCR4 signaling pathway, inhibited the recruitment of GFP(+) cells and negated completely the acceleration in tumor growth after operation (345 ± 172 mm(3), P < .05). CONCLUSION: Operative injury may induce the mobilization and recruitment of bone marrow stem cells, thereby enhancing angiogenesis and accelerating tumor growth. Inhibition of the SDF-1/CXCR4 signals may represent a new therapeutic strategy for preventing acceleration of tumor growth after operation.

DNA damage signaling is activated during cancer progression in human colorectal carcinoma.

PURPOSE: Recent studies have shown that the DNA damage response (DDR) is activated in precancerous lesions, suggesting that neoplastic cells may avoid apoptosis by impairing the DDR which acts as a barrier against tumor progression. To define the role of the DDR pathway in human colorectal carcinoma, we investigated the level of phosphorylated proteins of the DDR pathway. RESULTS: Immunostaining for pATM, gammaH2AX and pChk2 revealed that all were significantly expressed during tumor progression in advanced carcinoma (vs. normal tissue for pATM [p < 0.05]; vs. normal and adenoma for gammaH2AX [p < 0.05]; and vs. normal tissue for pChk2 [p < 0.05]. Western blot analysis of gammaH2AX and pChk2 revealed that their level increased gradually during tumor progression and was maximal in advanced carcinoma (vs. normal tissue; p < 0.05). No apoptotic cells were found in any tissue sample. EXPERIMENTAL DESIGN: Colorectal tissue samples were obtained at the time of surgery, from 55 patients at two hospitals. The tissues were classified into four groups according to pathology: normal mucosa, adenoma, early carcinoma and advanced carcinoma. We evaluated phosphorylated ataxia telangiectasia mutated (pATM), phosphorylated H2AX (gammaH2AX) and Chk2 (pChk2) protein levels by immunohistochemistry and western blot analysis. We also evaluated apoptosis by the TUNEL assay. CONCLUSIONS: The DDR pathway was activated during cancer progression, but no apoptosis was detected, even among the cells with activated DDR. It is likely that activation of DDR was induced by stress signaling as a consequence of oxidative, replication and mechanical stresses occurring during growth and expansion of the colorectal cancer.

[A case of multiple lung metastases of hepatocellular carcinoma after resection of liver and tumor thrombi in the inferior vena cava responding to chemotherapy using 5-FU, mitoxantrone and CDDP].

A 58-year-old man, who had a history of chronic type B hepatitis, was diagnosed as hepatocellular carcinoma with tumor thrombi in the inferior vena cava. He underwent resection of central bisegments and tumor thrombi, while postoperative chest CT demonstrated multiple lung metastases. Following 2 courses of chemotherapy using 5-FU, mitoxantrone, and CDDP (FMP therapy), multiple lung nodules disappeared and alpha-fetoprotein returned to the normal level. FMP therapy thus proved effective for a case of distant metastases of hepatocellular carcinoma.

Ectopic hepatocellular carcinoma arising in the bile duct.

We report a case of ectopic hepatocellular carcinoma arising in the bile duct. A 72-year-old woman was transferred to our hospital with fever, abdominal pain, and jaundice. Contrast-enhanced computed tomography revealed a round mass, measuring 25 mm in diameter, in the bile duct. The mass was causing obstructive jaundice. Endoscopic retrograde cholangiography showed a 27 mm x 21-mm round defect in the superior bile duct. These findings led to a diagnosis of bile duct tumor, and the patient underwent extrahepatic bile duct resection and biliary reconstruction. Gross examination of the tumor showed a fibrous capsule and a stalk arising from the bile duct mucosa. The tumor was diagnosed histopathologically as well-differentiated hepatocellular carcinoma arising in the bile duct.