Background. Although there are many reported prognostic indicators for pulmonary adenocarcinoma, the clinicopathologic characteristics and prognostic factors of early stage adenocarcinoma have not been evaluated fully, except for several studies of nonmucinous and sclerosing bronchioloalveolar carcinoma. Method. Two hundred thirty‐six surgically resected small peripheral adenocarcinomas measuring 2 cm or less in greatest dimension were reviewed using a simple histologic classification of six types based on tumor growth patterns. Results. Type A (localized bronchioloalveolar carcinoma [LBAC]) (n = 14) revealed replacement growth of alveolar‐lining epithelial cells with a relatively thin stroma. In type B (LBAC with foci of structural collapse of alveoli) (n = 14), fibrotic foci due to alveolar collapse were observed in tumors of LBAC. Type C (LBAC with foci of active fibroblastic proliferation) (n = 141) was the largest group in this study, and foci of active fibroblastic proliferation were evident. Type D (poorly differentiated adenocarcinoma), type E (tubular adenocarcinoma) and type F (papillary adenocarcinoma with a compressive growth pattern) (n = 61) showed compressive and expanding growth. Types A and B showed no lymph node metastasis and the most favorable prognosis (100% 5‐year survival) of the six types. Conclusion. Histologic types A and B are thought to be in situ peripheral adenocarcinoma, whereas type C appears to be an advanced stage of types A and B. Conversely, types D, E, and F are small advanced adenocarcinomas with a less favorable prognosis. Cancer 1995;75:2844–52.

The nuclear factor E2-related factor 2 (Nrf2) is a master transcriptional activator of genes encoding numerous cytoprotective enzymes that are induced in response to environmental and endogenously derived oxidative/electrophilic agents. Under normal, nonstressed circumstances, low cellular concentrations of Nrf2 are maintained by proteasomal degradation through a Keap1-Cul3-Roc1-dependent mechanism. A model for Nrf2 activation has been proposed in which two amino-terminal motifs, DLG and ETGE, promote efficient ubiquitination and rapid turnover; known as the two-site substrate recognition/hinge and latch model. Here, we show that in human cancer, somatic mutations occur in the coding region of NRF2, especially among patients with a history of smoking or suffering from squamous cell carcinoma; in the latter case, this leads to poor prognosis. These mutations specifically alter amino acids in the DLG or ETGE motifs, resulting in aberrant cellular accumulation of Nrf2. Mutant Nrf2 cells display constitutive induction of cytoprotective enzymes and drug efflux pumps, which are insensitive to Keap1-mediated regulation. Suppression of Nrf2 protein levels by siRNA knockdown sensitized cancer cells to oxidative stress and chemotherapeutic reagents. Our results strongly support the contention that constitutive Nrf2 activation affords cancer cells with undue protection from their inherently stressed microenvironment and anti-cancer treatments. Hence, inactivation of the Nrf2 pathway may represent a therapeutic strategy to reinforce current treatments for malignancy. Congruously, the present study also provides in vivo validation of the two-site substrate recognition model for Nrf2 activation by the Keap1-Cul3-based E3 ligase.cancer cell microenvironment ͉ multidrug resistant-associated protein ͉ oxidative stress ͉ somatic mutation ͉ ubiquitin-proteasome system

It has long been known that cell-cell adhesiveness is generally reduced in human cancers. Tumor cells are dissociated throughout the entire tumor masses of diffuse-type cancers , whereas those of solid tumors with high metastatic potentials are often focally dissociated or dedifferentiated at the invading fronts. Thus , both irreversible and reversible mechanisms for inactivating the cell adhesion system appear to exist. This paper focuses on the cadherin system, which mediates Ca 2؉ -dependent homophilic cell-cell adhesion. The E (epithelial)-cadherin-mediated cell adhesion system in cancer cells is inactivated by multiple mechanisms corresponding to the pathological features described above. Mutations have been found in the genes for E-cadherin and its undercoat proteins , ␣-and ␤-catenins, which connect cadherins to actin filaments and establish firm cell-cell adhesion. Transcriptional inactivation of E-cadherin expression was shown to occur frequently in tumor progression. E-cadherin expression in human cancer cells is regulated by CpG methylation around the promoter region. The cadherin system interacts directly with products of oncogenes , eg , c-erbB-2 protein and the epidermal growth factor receptor , and of the tumor suppressor gene , adenomatous polyposis coli (APC) protein , through ␤-catenin, which may be important in signal transduction pathways contributing to the determination of the biological properties of human cancers. In conclusion , inactivation of the E-cadherin system by multiple mechanisms , including both genetic and epigenetic events , plays a significant role in multistage carcinogenesis. (Am J Pathol 1998, 153:333-339) Cell-Cell Adhesion and Human CancersCell-cell adhesion participates in histogenesis and plays a critical role in the establishment and maintenance of cell polarity and cell society. It was known as early as the 1940s that the mutual adhesiveness of cancer cells is significantly weaker than that of the corresponding normal cells.1,2 Reduced cell-cell adhesiveness allows cancer cells to disobey the social order, resulting in destruction of the histological structure, the morphological hallmark of malignant tumors. In cancers in vivo, particularly the diffuse type, tumor cells are dissociated throughout the entire tumor masses, lose their cell polarity, and infiltrate the stroma in a scattered manner. One of the most characteristic features of cultured cancer cells in vitro is loss of "contact inhibition," which reflects disordered signal transduction from cell-cell adhesion to cell growth. Moreover, invasion and metastasis, which are the most life-threatening properties of malignant tumors, are considered to be later, but critically important, carcinogenetic steps. The invasion and metastatic processes themselves consist of sequential steps involving hosttumor interactions. In order for a metastatic nodule to form, cancer cells must leave the primary cancer nests, invade the surrounding host tissue, enter the circulation, lodge in a distant vascular bed, extravasate into ...

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