CXCL12-3' A polymorphism and lung cancer metastases protection: new perspectives in immunotherapy?

Abstract

Lung cancer remains a major worldwide health problem, being the most common form of cancer in the world, both in terms of incidence, 12.3% of all cancers (with an estimated 1.2 million new cases in 2000), and mortality (1.1 million deaths in 2000), representing 17.8% of the total number of deaths caused by cancer. More than half of the new cases occur in more developed countries (52%), with incidence rates lower in women (11.1 per 1,000,000), than in men (34.9 per 1,000,000) [17]. There are twomajor groups of lung carcinomas: smallcell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The latter includes epidermoid (squamous cell) carcinoma (which accounts for 25–40% of all lung cancers), adenocarcinoma and large cell carcinoma [5]. During the development of epidermoid carcinoma, oncogenic stimuli leads to a series of conversions of the normal bronchial epithelium, passing from premalignant lesions (hyperplastic, metaplastic, and dysplatic lesions) to carcinoma in situ that progresses to an overt carcinoma [19]. Adenocarcinomas are also thought to develop in part from premalignant precursor lesions such as atypical adenomatous hyperplasia [19]. Non-small cell lung cancer metastases to regional lymph nodes, liver, adrenal glands, contralateral lung, brain, and bone marrow are a key factor in the aggressiveness of this cancer [17] and experimental data have demonstrated that sites of metastases are determined both by the characteristics of neoplastic cells and the microenvironment of the specific organ [4]. Although tobacco smoking is pointed as the most important cause of lung cancers with 80–90% arising in cigarette smoker individuals [12], the biology of lung cancer is complex and poorly understood, and a variety of biomarkers have been implied in the virulence of this type of cancers [23]. Chemokines have recently emerged as an important family of proteins involved in tumourgenesis and organ-specific metastases [1, 13–15, 17, 21]. The chemokine receptor CXCR4 and its sole ligand SDF-1/ CXCL12 (Stromal Cell-Derived Factor-1) play important roles in inflammation and hematopoiesis, by acting as chemoattractant for leukocytes and stem cells [20]. Furthermore, it has been shown that in several types of cancer—including melanoma, ovarian, breast, and lung cancer—CXCL12 can stimulate the proliferation and/or survival of CXCR4-expressing cancer cells when they are grown under sub-optimal conditions, an adaptation that may allow tumour cells to grow in distant sites that would normally be less favourable [1]. The CXCR4-expressing metastatic cells might spread to many sites in the body, but only become established as metastatic locations where high levels of CXCL12 are found [1]. A single nucleotide polymorphism in the 3¢ untranslated region of the CXCL12 gene—CXCL12-3¢A—was reported as delaying AIDS progression to death [22, 24] and Zafiropoulos et al. associated the allelic frequency of the polymorphism with breast cancer and melanoma [25]. The aim of our study was to evaluate the genetic influence of CXCL12-3¢A polymorphism in the susceptibility to lung cancer development.