Metastatic Spread of Lung Cancer to Brain and Liver: Role of CX3CR1

Introduction

Lung cancer leads the ranking of cancer-related mortality in both the USA and Europe ( ). Non-small cell lung cancer (NSCLC) shows predominance over small cell histology (SCLC), which accounts for only 15–20% of the incident cases ( ). The biologic behavior of the two histological subgroups is inherently different, with SCLC being characterized by intense proliferative activity, higher propensity to early dissemination and intrinsic chemosensitivity ( ). Approximately 70% of newly diagnosed cases of SCLC present with extensive disease and, despite the generally favorable response rates to frontline chemotherapy, the life expectancy for these patients does not normally exceed 12 months ( ).

NSCLC represents a heterogeneous aggregate of histologies including squamous cell, adenocarcinoma and large cell carcinoma. Recent advances in the genetic characterization of NSCLC have enriched such classification introducing molecularly defined tumor phenotypes. The presence of epithelial growth factor receptor (EGFR) activating mutations, for example, defines a subgroup of NSCLC affecting approximately 50% of Asian patients and 10% of non-Asians, that are more likely to respond to EGFR tyrosine kinase inhibitors. More recent work on novel targets such as anaplastic lymphoma kinase (ALK) rearrangements, which identify 2–7% of adenocarcinomas with favorable response rates to ALK inhibitors, has further strengthened the concept of molecular classification of NSCLC ( ).

In the context of such a molecularly composite disease, Tumor Node Metastasis (TNM) staging remains a solid guide to treatment allocation and holds prognostic significance. In fact, while patients presenting with either surgically unresectable (stage IIIB) or metastatic tumors (stage IV) will inevitably succumb from their disease, those with operable NSCLC may potentially hope for a cure, with 5-year survival probabilities ranging from 80% for stage IA, to 30% for stage IIIA ( ).

Regardless of histology, metastatic diffusion is viewed as the main factor that influences treatment failure in the curative setting ( ), reduces the chances of long-term survival as a result of organ failure and determines the symptomatic burden typically affecting patients with advanced cancer. Metastatic dissemination to the liver and the central nervous system (CNS) is fairly common in the evolution of bronchogenic carcinoma. However, the development of metastatic spread to these districts remains difficult to predict in the individual patient.

Intracranial diffusion is the most common pattern of treatment failure in patients who present with potentially curable NSCLC ( ), and eventually affects up to 55% of the patients with locally advanced disease ( ). Cerebral metastases have an invariably fatal clinical course and represent the direct cause of death in these patients ( ). Although a number of clinical predictors of metastatic spread to the CNS including nodal status and non-squamous histology have been identified, the precise molecular mechanisms contributing to the neurotropic potential of lung cancer cells have not been fully elucidated.