PubMed · 13776038
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J L TERRY, J C GAISFORD, D C HANNA. 1961. Pilonidal sinus carcinoma.. https://doi.org/10.1016/0002-9610(61)90538-4
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Amphicrine carcinomas of the stomach, defined by dual exocrine and neuroendocrine differentiation within the same neoplastic cell, are exceedingly rare. MUTYH-associated polyposis (MAP) is an autosomal recessive polyposis syndrome characterized by multiple colorectal adenomas and variable upper gastrointestinal involvement; however, amphicrine carcinomas have not been previously documented in this setting. We report a gastric amphicrine carcinoma arising in the background of extensive fundic gland polyposis in a patient with MAP. Endoscopy revealed a 3.5-cm flat elevated lesion in the gastric fundus amid extensive fundic gland polyposis. Histologically, the tumor consisted of a single population of cells exhibiting combined glandular and neuroendocrine differentiation without zonal or biphasic architecture, and many of these cells demonstrated true amphicrine morphology. Immunohistochemistry confirmed co-expression of cytokeratin and the neuroendocrine markers chromogranin A and synaptophysin in the same cell population. Germline targeted next-generation sequencing identified biallelic MUTYH variants in trans (c.733C>T, p.Arg245Cys [likely pathogenic]; c.842C>T, p.Ala281Val [variant of uncertain significance]), supporting a diagnosis of MAP. To our knowledge, this is the first reported case of a gastric amphicrine carcinoma in a MAP patient, expanding the spectrum of MAP-associated upper gastrointestinal neoplasia and underscoring the importance of vigilant endoscopic surveillance in hereditary polyposis syndromes.
Infection of specific types of 'high risk' HPVs such as HPV 16 and HPV 18 has been associated with the development of cervical cancer. Deregulation of specific NF-kappaB members has also been implicated with the development of many cancers including cervical cancer. We have studied the expression and DNA-binding activity of NF-kappaB during the development of cervical cancer involving cervical precancer, cancer and control tissues with or without HPV infection. We observed constitutive activation of NF-kappaB to a significant level in squamous-cell carcinomas while no or negligible NF-kappaB binding activity was observed in normal controls or precancerous lesions. Interestingly, there is a gradual increase in binding activity and expression of NF-kappaB from low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesion (HSIL) and to invasive squamous cell carcinoma (SCC). On further dissection of NF-kappaB complex, the p50 subunit which generally heterodimerizes with p65 to form an active form NF-kappaB appears to form a p50/p50 homodimer instead of conventional p50/p65 heterodimer. In situ analysis of expression of p50 and p65 subunits by immunohistochemistry in tissue sections from different grades of cervical lesions including invasive cancer also demonstrate a gradual increase in the expression and nuclear localization of p50 subunit only as the severity of lesions increases. We have observed a very high expression of nuclear p50 in HSIL and invasive cancers while the level of nuclear p65 is significantly lower or nil. We further observed that this activation is not dependent on HPV infection since both HPV positive and HPV negative tumors showed the same pattern of high binding activity and increased expression of NF-kappaB p50/p50 homodimer. Although nuclear translocation and localization of p65 was observed to a lesser extent in invasive tumor, p65 was not found to be involved in dimmer formation. Thus the gradual activation and expression of NF-kappaB as a function of severity of cervical lesions and the change in dimerization pattern in favor of p50/p50 homodimers appears to play an important role during the development of cervical carcinoma.
Indomethacin, a common nonsteroidal anti-inflammatory drug, has been shown to enhance radiation-mediated cell-killing effect through the activation of p38 mitogen-activated protein kinase (MAPK). We found that indomethacin strongly reduced the basal level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in HT-29 human colon carcinoma cells. The inhibition of ERK1/2 by indomethacin was only observed in cells with high basal activities of ERK1/2 such as HT-29 cells, but not in cells with low basal activities, such as HeLa. Cell cycle analysis of HT-29 cells exposed with indomethacin showed a partial G1/S arrest and slow DNA synthesis. However, the treatment with NS398, a specific COX-1/2 inhibitor, failed to show any effect on cell cycle, indicating that the inhibition of COX-1/2 is not responsible for cell cycle arrest. Since U0126, a specific inhibitor for MEK1/2, also induced a partial G1/S arrest, the G1/S arrest induced by indomethacin is, at least in part, caused by the inhibition of ERK1/2. Cell proliferation of HT-29 was inhibited by the treatment of U0126 but not in HeLa cells, and the treatment of HT-29 cells with U0126 enhanced radiation sensitivity possibly due to the accumulation of cells in G1 phase. We found that 17-allylamino-17-demethoxygeldanamycin, a geldanamycin delivative, radiosensitized HT-29 cells at a relatively low dose of irradiation, and indomethacin and U0126 further enhanced this effect. Therefore, tumor cells with elevated ERK1/2 activity can be effectively sensitized to radiation treatment by a combinational inhibition of HSP90 and MAPK activity.