Lung Cancer: New Therapeutic Targets, New Definitions

Lung cancer is the leading cause of cancer death for men and women in the United States (1). This high mortality rate is heavily influenced by the fact that most lung cancers, in contrast to cancers such as breast and colon, are diagnosed at an advanced stage when metastases are present and cure is no longer an option (2). Because of this fact, the 5-year mortality for lung cancer has unfortunately remained relatively unchanged for the past 40 years. Although recent advances in lung cancer screening might alter this landscape in favor of diagnosing more early-stage, resectable tumors, a better understanding of the mechanisms behind lung cancer pathogenesis and the factors that promote metastasis is needed to design new therapies and treatment strategies.

In the current issue of the Journal, Antón and colleagues (pp. 96–105) present their findings on the role of the endogenous anticoagulant activated protein C (APC) and its receptor, the endothelial protein C receptor (EPCR), in lung cancer metastasis (3). There are two key findings in their studies: APC–EPCR is a novel signaling axis involved in metastasis of lung adenocarcinoma, and tumor EPCR expression might carry prognostic information for adenocarcinoma patients.

Protein C (PC) and APC are central participants in coagulation. PC is a plasma serine protease that circulates as an inactive zymogen. As the coagulation cascade is triggered, the protease thrombin forms a complex with the endothelial surface protein thrombomodulin (TM). This thrombin/TM complex then converts PC to its active form, APC. APC inactivates factors Va and VIIIa, which, in turn, block downstream thrombin generation and further PC activation. EPCR is a crucial participant in the PC/APC pathway (4) as it binds PC and presents it to the thrombin/TM complex, thereby increasing the activation of PC to APC by approximately 20-fold (5, 6).

But what is the relationship of this hemostatic cascade to lung cancer metastasis? Importantly, APC also binds EPCR, and increasing evidence indicates that much, if not all, of APC intracellular signaling is EPCR dependent. This signaling is directly relevant to cancer. In an EPCR-dependent fashion, APC inhibits p53-dependent apoptosis (7), decreases Rac- and Akt-mediated cell–cell adhesion, and enhances tumor cell invasion and migration (8–10), directly affecting cell survival and a cancer’s metastatic potential. Although APC does not appear to affect cancer cell proliferation, it increases endothelial cell proliferation and is proangiogenic via up-regulation of endothelial nitric oxide synthase (11), thereby increasing vascular supply to the tumor. In addition, EPCR serves as a docking protein for other receptors such as the protease-activated receptor 1 (PAR1) and the sphingosine 1-phosphate receptor 1 (S1P1 or Edg1), both of which are linked to the transformation process. Finally, APC-EPCR inhibits lymphocyte migration (12) and production of interferon-γ by natural killer cells (13), which may impair immune surveillance of tumors. These functions imply that APC and EPCR have the potential to significantly influence cancer cell growth, survival, and metastasis.

Anton and colleagues convincingly demonstrate, using in vitro, in vivo, and human studies, that EPCR affects lung adenocarcinoma metastasis. Using a murine metastasis model in which cells from an adenocarcinoma cell line are seeded hematogenously via intracardiac puncture, decreasing cancer cell EPCR expression using an RNA interference strategy or a pharmacologic inhibitor decreased metastases. In contrast, increased EPCR expression increased metastases. The authors also confirmed the previously identified finding that APC attenuates apoptosis in vitro, and although this was not specifically tested in their model, suggest that decreased metastases might be through an APC-induced prosurvival mechanism in cancer cells.

Perhaps most striking, the authors demonstrated that EPCR expression by pulmonary adenocarcinomas was both prognostic and predictive of response to therapy. Using retrospective data from two clinical trials, the authors separated participants into cohorts of high and low tumor EPCR expression and found that high EPCR expression predicted shorter metastasis-free and total survival. In addition, patients with stage I adenocarcinomas that had high EPCR expression and received postsurgical adjuvant therapy had an overall and progression-free survival benefit, though these analyses had relatively small populations. Although the authors do not comment on the presence of other high-risk features, this effect was independent of tumor size, age, sex, and smoking status, suggesting that tumor EPCR expression carries prognostic information. Thus, EPCR expression status might be used to identify patients that could benefit from further therapy or to guide therapy if EPCR antagonists are found to be effective against lung cancer.

Anton and colleagues have pointed out a new pathway that potentially promotes lung adenocarcinoma spread and could lead to novel therapeutic targets to control metastases, including APC, EPCR, and possibly other intracellular partners such as PAR1 or S1P1. The benefit of such an approach is yet to be determined and will require further evaluation. However, their findings again highlight that lung cancer management is moving beyond the use of pure clinicopathologic classifications and staging to include molecular characterization, creating new designations of lung cancer to refine our therapeutic and prognostic capabilities. The identification of specific “driver” mutations in lung cancer, such as EGFR, has expanded our understanding of oncogenesis and lung cancer care as targeted therapy directed against the mutant protein results in dramatic clinical improvements (14). Expression levels of genes and proteins that do not have somatic mutations also provide prognostic and predictive information in lung cancer. For example, low excision repair cross-complementation group 1 (ERCC1) expression portends a poor prognosis in non–small cell lung cancer but also predicts a better response to platinum-based therapy when compared with high ERCC1–expressing tumors (15). If the findings concerning EPCR are confirmed, EPCR would add to this expanding panel of markers and targets in lung adenocarcinomas to move toward a more refined, molecularly based taxonomy and therapy of lung cancer.