Adenocarcinoma News Headlines

Morphoproteomic profile of mTOR, Ras/Raf kinase/ERK, and NF-kappaB pathways in human gastric adenocarcinoma.

Ann Clin Lab Sci. 2008;38(3):195-209

Authors: Feng W, Brown RE, Trung CD, Li W, Wang L, Khoury T, Alrawi S, Yao J, Xia K, Tan D

Preclinical studies using human gastric adenocarcinoma (GAC) cell lines have shown that the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, can inhibit tumor growth and that the extracellular signal-regulated kinase (ERK) of the Ras/Raf kinase/ERK pathway is related to chemoresistance and apoptosis. We examined the state of activation of components of mTOR, Ras/Raf kinase/ERK, and nuclear factor (NF)-kappaB signal transduction pathways, as well as cell cycle protein analyte correlates in GAC cases. Formalin-fixed paraffin-embedded tissue microarray blocks containing samples from 210 cases of GAC were examined. Immunohistochemistry was utilized to detect the following antigens: S100P, upstream stimulator of ERK, and NF-kappaB pathways; phosphorylated (p)-mTOR (Ser 2448), p-ERK-1/2 (Thr 202/Tyr 204), and one of their common down-stream effectors, p-p70S6K(Thr 389); p-NF-kappaBp65(Ser 536); and cell cycle associated proteins, Ki-67, and S phase kinase-associated protein (Skp)2. Immunoreactivity (0 to 4+) of protein expression and compartmentalization were assessed by bright-field microscopy. The majority of cases showed positive (1+ to 4+) cytoplasmic/plasmalemmal p-mTOR (88%), and moderate-strong (2+ to 4+) nuclear p-p70S6K (93%) and nuclear S100P (81%) expression. A subset of cases exhibited moderate-strong nuclear p-ERK-1/2 (15%) and p-NF-kappaBp65 (36%) expression. The majority of cases showed concomitant moderate-strong (2+ to 4+) nuclear Ki-67 (71%) and Skp2 (68%). Nuclear expression levels of p-ERK-1/2 and p-NF-kappaBp65, of p-p70S6K and p-NF-kappaB, and of Ki-67 and Skp2, respectively, showed significant linear correlations in GAC (p <0.001). Additionally, there were statistically significant differences in the mean expression levels of p-ERK-1/2 and p-NF-kappaBp65 in diffuse vs intestinal types of GAC, with higher levels of both in the diffuse type ( p = 0.001 and p <0.0001, respectively). In summary, morphoproteomic analysis reveals constitutive activation of mTOR and to some extent, Ras/Raf kinase and NF-kappaB pathways in GAC, as evidenced by increased cytoplasmic p-mTOR, nuclear translocation of p-p70S6K and p-ERK-1/2 phosphorylated at putative sites of activation (Ser 2448, Thr 389, and Thr 202/Tyr 204, respectively), as well as correlative expression of cell cycle analytes, Ki-67, and Skp2. These results suggest that a prospective study is warranted to evaluate the use of morphoproteomic profiling of individual patients with GAC in order to design combinatorial treatment strategies that target the mTOR, Ras/Raf kinase/ERK, and/or NF-kappaB pathways.

PMID: 18715846 [PubMed - in process]

MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

J Immunol. 2008 Sep 1;181(5):3116-25

Authors: Tinder TL, Subramani DB, Basu GD, Bradley JM, Schettini J, Million A, Skaar T, Mukherjee P

MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.

PMID: 18713982 [PubMed - in process]

Cutaneous metastatic adenocarcinoma arising from a malignant sacrococcygeal teratoma in an adult.

Dermatol Online J. 2008;14(6):3

Authors: Savk E, Kolay A, Meteoglu I, Unsal A, Cevikel H, Uslu M, Karaman G, Sendur N, Erdoğdu I

We present a patient with cutaneous metastasis caused by an adenocarcinoma arising from a malignant teratoma. A 37-year-old woman seen for the complaint of swelling in the genital region also complained of a draining mass in her gluteal region present since birth. Physical examination showed marked edema in the labia majora, multiple hyperkeratotic papules in the left labium majus, and erythema, induration, and swelling in the left femoral and inguinal regions. A soft tumor that exhibited sinus tracts was palpated in the left gluteus. Excision of the gluteal tumor revealed a teratoma. Vulvar skin biopsy confirmed a mucinous adenocarcinoma which had derived from this teratoma. A tumor that arises from pluripotent germ cells, teratoma rarely shows malignant transformation. The patient presented is a rare example of a cutaneous metastasis originating from a congenital sacrococcygeal teratoma in an adult.

PMID: 18713584 [PubMed - in process]

Co-opted JNK/SAPK signaling in Wnt/beta-catenin-induced tumorigenesis.

Neoplasia. 2008 Sep;10(9):1004-13

Authors: Liu B, Yu HM, Huang J, Hsu W

Aberrant stimulation of the canonical Wnt pathway induces mammary tumorigenesis in mice. It has been well documented that two types of tumors, adenocarcinoma and adenocarcinoma with squamous metaplasia, develop in these mutants. However, the molecular mechanism underlying the induction of squamous transdifferentiation remains largely unknown. Here, we show that JNK/SAPK signaling plays an important role in Wnt-dependent mammary development and malignant transformation. The JNK/SAPK pathway is stimulated in pregnancy-mediated lobulo-alveolar morphogenesis, a process highly dependent on Wnt/beta-catenin signaling. Strong elevations of JNK/SAPK signaling are associated with squamous metaplasia of the Wnt-induced adenocarcinoma. Reconstitution of beta-catenin and JNK/SAPK signaling activities also promotes expression of the squamous cell marker in cultured epithelial cells. Furthermore, a synergistic activation of these two pathways can be identified in the malignant squamous cells of human endometrial and lung cancers. This is potentially a significant discovery in modern cancer therapy because of the effectiveness of an angiogenesis inhibitor, Avastin, for the treatment of adenocarcinoma, but not squamous cell carcinoma, in human lung cancers. Our finding may improve the usage of biomarkers to distinguish these two poorly differentiated tumor types, sharing similar histologic features.

PMID: 18714362 [PubMed - in process]

Prognostic relevance of hTERT mRNA expression in ductal adenocarcinoma of the pancreas.

Neoplasia. 2008 Sep;10(9):973-6

Authors: Grochola LF, Greither T, Taubert HW, Möller P, Knippschild U, Udelnow A, Henne-Bruns D, Würl P

Telomerase is thought to play an essential role in tumorigenesis and progression. Its activity is directly correlated with the expression of its catalytic subunit, human telomerase reverse transcriptase (hTERT). A correlation of transcript expression with a poor prognosis has been detected in different human malignancies. However, data on hTERT in pancreatic ductal adenocarcinoma (PDAC) are purely descriptive so far. Therefore, we evaluated the impact of hTERT expression on patients' prognosis. Human telomerase reverse transcriptase mRNA isolates from 56 human microdissected PDAC tissues were analyzed by quantitative reverse transcription-polymerase chain reaction and multivariate Cox regression hazard test. Elevated hTERT transcript levels were measured in 23 of 56 PDAC tissues, 33 patients showed no detectable transcripts. Unexpectedly, a low expression of hTERT mRNA levels was associated with a worse prognosis for overall survival (relative risk = 5.33; P = .013) when compared to high levels, whereas undetectable expression showed an intermediate risk of tumor-related death. These data challenge previous findings outlining hTERT's negative impact on overall survival. The risk pattern obtained in PDAC suggests a more complex regulation of hTERT.

PMID: 18714398 [PubMed - in process]

Synergism of CPT-11 and Apo2L/TRAIL against Two Differentially Sensitive Human Colon Tumor Xenografts.

Oncology. 2008 Aug 20;74(3-4):188-197

Authors: Sugamura K, Gibbs JF, Belicha-Villanueva A, Andrews C, Repasky EA, Hylander BL

Objective: The ability to sustain and grow portions of human tumors as xenografts in SCID mice provides a valuable preclinical opportunity to test the response of human tumors to treatments, both individually and in combination. Using this model, our laboratory has previously demonstrated that the growth of several human adenocarcinomas can be inhibited by Apo2L/TRAIL. Apo2L/TRAIL triggers apoptosis in many types of tumor cells, and when combined with various chemotherapeutic agents results in enhanced inhibition of tumor growth in many xenograft models. Methods: To gain further insight into the antitumor potential of Apo2L/TRAIL in combination with chemotherapy, we compared the responses of 2 human colon adenocarcinomas, both of which were sensitive to CPT-11 while one was sensitive and the other comparatively resistant to Apo2L/TRAIL. Results: In both cases, a greater degree of growth inhibition was achieved when these agents were used in combination. Western blot analysis demonstrated that in the Apo2L/TRAIL-sensitive tumor total cellular expression of Apo2L/TRAIL death receptors (DR4 and DR5) as well as protein expression of the pro-apoptotic molecule BAX were higher and the anti-apoptotic molecule Bcl-2 was lower in comparison to the Apo2L/TRAIL-resistant tumor. Conclusion: These results indicate that both Apo2L/TRAIL-sensitive and -resistant colon tumors will respond to a combination of CPT-11 and Apo2L/TRAIL and predict that this will be useful in the treatment of human colon cancers in a clinical setting.

PMID: 18714167 [PubMed - as supplied by publisher]

Human papillomavirus infection in Barrett's oesophagus in the UK: An infrequent event.

J Clin Virol. 2008 Aug 19;

Authors: Rai N, Jenkins GJ, McAdam E, Hibbitts SJ, Fiander AN, Powell NG

BACKGROUND: Human papillomavirus (HPV) infection has been reported in squamous cell carcinomas of the oesophagus and has been recently described in Barrett's oesophagus, a premalignant condition which may give rise to oesophageal adenocarcinoma. OBJECTIVES: To investigate HPV infection in Barrett's oesophagus in a UK population. STUDY DESIGN: DNA was extracted from 73 Barrett's oesophagus biopsies and examined for the presence of DNA for 14 high risk (HR) and 6 low risk (LR) HPV types. RESULTS: HPV DNA was present in only 1 of 73 samples; genotyping indicated this was a high risk type 51 infection. CONCLUSIONS: HPV infection appears unlikely to be a significant factor in the aetiology of Barrett's oesophagus in the UK.

PMID: 18718811 [PubMed - as supplied by publisher]