To investigate genes involved in pulmonary carcinogenesis and those related to sensitivity of nonsmall cell lung cancers (NSCLCs) to therapeutic drugs, we performed cDNA microarray analysis of 37 NSCLCs after lasercapture microdissection of cancer cells from primary tumors. A clustering algorithm applied to the expression data easily distinguished two major histological types of non-small cell lung cancer, adenocarcinoma and squamous cell carcinoma. Subsequent analysis of the 18 adenocarcinomas identified 40 genes whose expression levels could separate cases with lymph-node metastasis from those without metastasis. In addition, we compared the expression data with measurements of the sensitivity of surgically dissected NSCLC specimens to six anti-cancer drugs (docetaxel, paclitaxel, irinotecan, cisplatin, gemcitabine, and vinorelbine), as measured by the CD-DST (collagen gel droplet embedded culture-drug sensitivity test) method. We found significant associations between expression levels of dozens of genes and chemosensitivity of NSCLCs. Our results provide valuable information for eventually identifying predictive markers and novel therapeutic target molecules for this type of cancer.

The micropapillary pattern is characterized by small papillary tufts with no fibrovascular core lying in spaces and has been reported as an aggressive variant of carcinoma in several organs. We investigated the histopathobiological properties of the micropapillary pattern with immunohistochemistry, serial sections, and electron microscopy in lung adenocarcinoma. We further analyzed its clinicopathological character and prognosis. The subjects included 383 adenocarcinoma cases, of which 184 (48%) were micropapillary patternpositive and 199 (52%) were micropapillary pattern-negative. On histology, micropapillary tufts seemed to float in the alveolar space or spaces encased by connective tissues, whereas serial sections revealed that most tufts had continuity with other tufts and even with the main tumor. Positive staining for the adhesion molecules E-cadherin and b-catenin suggested the preservation of tight adhesion, and electron microscopy showed the existence of intercellular junctions. Negative staining for laminin and loss of basement membrane as determined by electron microscopy suggest a loss of cell-matrix contact. Positive staining for Ki-67 indicates that cells constituting micropapillary tufts retained their proliferation potency. There were no CD34-positive cells in micropapillary tufts, and the loss of the vascular core was confirmed. In micropapillary pattern-positive cases, lymphatic invasion was identified significantly more frequently than in micropapillary pattern-negative cases (Po0.001), even at stageIA (without lymph node metastasis, N ¼ 197) (Po0.001). The 5-year and 10-year overall survival rates of the micropapillary pattern-positive stageIA group were 77.6 and 67.6%, respectively, which were significantly less than those of the micropapillary pattern-negative stageIA group (98.1 and 98.1%) (P ¼ 0.001). In conclusion, cells constituting the micropapillary pattern are likely to have acquired anchorage-independent growth and a potential for high malignancy.

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We should utilize these prognostic factors to detect patients who might benefit from surgery. Therefore, we should periodically follow up advanced colorectal cancer patients by chest computed tomography to detect small pulmonary metastases before serum CEA elevation. Metastases to the lung or organs upstream from the lung are regarded as semi-local for colorectal cancer. This concept provides a rationale for validating surgical indications for pulmonary metastases from colorectal cancer.

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