Protein kinase C (PKC) isozymes have long been implicated in carcinogenesis. However, little is known about the functional significance of these enzymes in human cancer. We recently showed that the atypical PKC (aPKC) isozyme PKCι is overexpressed in human non–small cell lung cancer (NSCLC) cells and that PKCι plays a critical role in the transformed growth of the human lung adenocarcinoma A549 cell line in vitro and tumorigenicity in vivo. Here we provide compelling evidence that PKCι is an oncogene in NSCLC based on the following criteria: (a) aPKCι is overexpressed in the vast majority of primary NSCLC tumors; (b) tumor PKCι expression levels predict poor survival in patients with NSCLC; (c) the PKCι gene is frequently amplified in established NSCLC cell lines and primary NSCLC tumors; (d) gene amplification drives PKCι expression in NSCLC cell lines and primary NSCLC tumors; and (e) disruption of PKCι signaling with a dominant negative PKCι allele blocks the transformed growth of human NSCLC cells harboring PKCι gene amplification. Taken together, our data provide conclusive evidence that PKCι is required for the transformed growth of NSCLC cells and that the PKCι gene is a target for tumor-specific genetic alteration by amplification. Interestingly, PKCι expression predicts poor survival in NSCLC patients independent of tumor stage. Therefore, PKCι expression profiling may be useful in identifying early-stage NSCLC patients at elevated risk of relapse. Our functional data indicate that PKCι is an attractive target for development of novel, mechanism-based therapeutics to treat NSCLC.

Context.— Amyloidosis is a heterogeneous group of diseases characterized by the deposition of congophilic amyloid fibrils in the extracellular matrix of tissues and organs. To date, 31 fibril proteins have been identified in humans, and it is now recommended that amyloidoses be named after these fibril proteins. Based on this classification scheme, the most common forms of amyloidosis include systemic AL (formerly primary), systemic AA (formerly secondary), systemic wild-type ATTR (formerly age-related or senile systemic), and systemic hereditary ATTR amyloidosis (formerly familial amyloid polyneuropathy). Three different clinicopathologic forms of amyloidosis can be seen in the lungs: diffuse alveolar-septal amyloidosis, nodular pulmonary amyloidosis, and tracheobronchial amyloidosis. Objective.— To clarify the relationship between the fibril protein–based amyloidosis classification system and the clinicopathologic forms of pulmonary amyloidosis and to provide a useful guide for diagnosing these entities for the practicing pathologist. Data Sources.— This is a narrative review based on PubMed searches and the authors' own experiences. Conclusions.— Diffuse alveolar-septal amyloidosis is usually caused by systemic AL amyloidosis, whereas nodular pulmonary amyloidosis and tracheobronchial amyloidosis usually represent localized AL amyloidosis. However, these generalized scenarios cannot always be applied to individual cases. Because the treatment options for amyloidosis are dependent on the fibril protein–based classifications and whether the process is systemic or localized, the workup of new clinically relevant cases should include amyloid subtyping (preferably with mass spectrometry–based proteomic analysis) and further clinical investigation.

Small cell lung carcinoma (SCLC) is characterized by high metastatic rate and poor prognosis. The platinum-based chemotherapy still represents the backbone of the therapy; however, acquired resistance develops almost in all patients. Although SCLC has been formerly considered a homogeneous disease, recent advances in SCLC research have highlighted the importance of inter- and intratumoral heterogeneity and have resulted in the subclassification of SCLC. The newly described SCLC subtypes are characterized by distinct biological behavior and vulnerabilities that can be therapeutically exploited. The PI3K/Akt/mTOR pathway is frequently affected in SCLC, and its activation represents a promising therapeutic target. Since the mTOR pathway is a master regulator of cellular metabolism, its alterations may also influence the bioenergetic processes of SCLC cells. Despite the encouraging preclinical results, both mTOR and metabolic inhibitors have met limited clinical success so far. Patient selection for personalized therapy, the development of rational drug combinations, and a better understanding of heterogeneity and spatiotemporal evolution of the tumor cells may improve efficacy and can help to overcome acquired resistance. Here we provide a summary of current investigations regarding the role of the mTOR pathway and metabolic alterations in the progression and metastasis formation of SCLC.