Metabolomic Profiling of Lung CAFs
Cancer cells undergo a well-described metabolic reprogramming that is important for tumorigenesis. However, metabolic reprogramming in non-epithelial cells residing in the tumor microenvironment has not been examined in detail. Chaudhri and colleagues performed comprehensive mass-spectrometry–based metabolic profiling to uncover several metabolic pathways that distinguish cancer-associated fibroblasts (CAF) from adjacent “normal” fibroblasts as well as distinguishing CAFs from high- versus low-glycolytic tumors. One such change was an increase in dipeptides from CAFs, which was positively correlated with the glycolytic activity of their parent tumor. This increase in dipeptides was associated with upregulated basal macroautophagy, indicating that augmented catabolism was responsible for the increase in dipeptides. These results demonstrate that metabolic reprogramming and increased macroautophagy are not limited to cancer cells of the tumor, thereby establishing the importance of understanding the role of this metabolic reprogramming in the protumorigenic activities of CAFs.
PPP2R2C-Mediated Prostate Cancer Growth
Prostate cancer, including metastatic disease, is largely dependent on androgen receptor (AR) signaling. Despite initially effective androgen deprivation therapies (ADT), disease recurrence is common and may involve circumventing AR ligand-mediated pathways. To test this hypothesis, Bluemn and colleagues used a high-throughput RNA interference screening approach to identify 40 high-confidence targets that, when lost, drive growth under conditions that mimic ADT. Two components (PPP2R: 1A and 2C) of the protein phosphatase 2 (PP2A) complex were shown to be downregulated as a function of disease progression. Additional investigation revealed that PPP2R2C loss was sufficient to promote bypass of enzalutamide-based ADT, and immunohistochemical stratification of PPP2R2C levels in patient specimens indicated a significant association between low PPP2R2C levels and increased recurrence and mortality. The results of this study not only define PPP2R2C as a new player in the mechanisms of ADT resistance but also suggest prognostic and therapeutic potential.
mda-7/IL-24 Suppresses Breast Cancer through GAS3
The cytokine mda-7/interleukin (IL)-24 has been suggested to function as a tumor suppressor in a number of solid tumor types and to promote cancer-specific cell death in a context-dependent manner. Li and colleagues reveal that mammary tumorigenesis in rats was suppressed by single administration of an adenovirus-expressing mda-7/IL-24. Mechanistically, mda-7/IL-24 induced the expression of growth arrest–specific gene 3 (GAS3/PMP22) to inhibit the attachment and proliferation of tumor cells in part by blocking the interaction of β1-integrin with fibronectin. Using primary human breast cancer specimens, they found a positive correlation between the expression of the IL-24 receptor (IL20RA) and GAS3. Moreover, IL20RA expression was correlated with metastasis-free survival in HER2+ patient samples. Thus, a novel GAS3-integrin/fibronectin inhibitory pathway has been identified downstream of mda-7/IL-24 that can be targeted for therapy.
Oncogenic Transformation of Human Lung Epithelial Cells
To understand the pathogenesis of lung cancer and identify new therapeutic targets, it is crucial to develop new preclinical model systems. Sato and colleagues demonstrate that nonmalignant CDK4/hTERT–immortalized human bronchial epithelial cells (HBEC) can be progressed to fully malignant cells capable of in vivo tumor formation, representing the gamut of non–small cell lung cancer (NSCLC) histologies, following the introduction of defined oncogenic alterations (oncogenic KRAS, p53 knockdown, and c-MYC overexpression) that mimic genetic alterations commonly found in NSCLC. Genomic data show that human lung cancers exhibit a large number of sequence-altering mutations that require sorting out of “passenger” and “driver” changes. Therefore, the HBEC model provides a mechanism to test these candidates and identify the minimal, most crucial set of alterations required for full malignant transformation of lung epithelial cells.
- ©2012 American Association for Cancer Research.