CSF-1 and Ang-2 serum levels - prognostic and diagnostic partners in non-small cell lung cancer.

BACKGROUND: Lung cancer is the most incident and lethal form of cancer, with late diagnosis as a major determinant of its bad prognosis. Immunotherapies targeting immune checkpoints improve survival, but positive results encompass only 30%-40% of the patients, possibly due to alternative pathways to immunosuppression, including tumour-associated macrophages (TAM). Colony stimulating factor-1 (CSF-1) is implicated in TAM differentiation and recruitment to tumours and in tumour angiogenesis, through a special setting of Tie-2-expressing macrophages, which respond to angiopoietin-2 (Ang-2). We evaluated the role of serum levels of CSF-1 in non-small cell lung cancer (NSCLC) prognosis and whether these could serve as biomarkers for NSCLC detection, along with Ang-2. PARTICIPANTS AND METHODS: We prospectively studied an unselected cohort of 145 patients with NSCLC and a group of 30 control individuals. Serum levels of Ang-2 and CSF-1 were measured by ELISA prior to treatment. RESULTS: Serum levels of CSF-1 and Ang-2 are positively correlated (p<0.000001). Individuals with high serum levels of CSF-1 have a 17-fold risk for NSCLC presence and patients with combined High Ang-2/CSF-1 serum levels present a 5-fold increased risk of having NSCLC. High Ang-2/CSF-1 phenotype is also associated with worst prognosis in NSCLC. CONCLUSIONS: Combined expression of CSF-1 and Ang-2 seems to contribute to worst prognosis in NSCLC and it is worthy to understand the basis of this unexplored partnership. Moreover, we think CSF-1 could be included as a biomarker in NSCLC screening protocols that can improve the positive predictive value of the current screening modalities, increase overall cost effectiveness and potentially improve lung cancer survival.

Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches?

The critical role of angiogenesis in tumor development makes its inhibition a valuable new approach in therapy, rapidly making anti-angiogenesis a major focus in research. While the VEGF/VEGFR pathway is the main target of the approved anti-angiogenic molecules in NSCLC treatment, the results obtained are still modest, especially due to resistance mechanisms. Accumulating scientific data show that vessel co-option is an alternative mechanism to angiogenesis during tumor development in well-vascularized organs such as the lungs, where tumor cells highjack the existing vasculature to obtain its blood supply in a non-angiogenic fashion. This can explain the low/lack of response to current anti-angiogenic strategies. The same principle applies to lung metastases of other primary tumors. The exact mechanisms of vessel co-option need to be further elucidated, but it is known that the co-opted vessels regress by the action of Angiopoietin-2 (Ang-2), a vessel destabilizing cytokine expressed by the endothelial cells of the pre-existing mature vessels. In the absence of VEGF, vessel regression leads to tumor cell loss and hypoxia, with a subsequent switch to a neoangiogenic phenotype by the remaining tumor cells. Unravelling the vessel co-option mechanisms and involved players may be fruitful for numerous reasons, and the particularities of this form of vascularization should be carefully considered when planning anti-angiogenic interventions or designing clinical trials for this purpose. In view of the current knowledge, rationale for therapeutic approaches of dual inhibition of Ang-2 and VEGF are swiftly gaining strength and may serve as a launchpad to more successful NSCLC anti-vascular treatments.

Combined Ang-2 and VEGF serum levels: holding hands as a new integral biomarker in non-small-cell lung cancers.

AIM: Evaluate if serum levels of VEGF and Ang-2 are correlated in non-small-cell lung cancers (NSCLCs) and its implications in the diagnostic and prognostic of the disease. PATIENTS & METHODS: Unselected cohort of 145 NSCLC patients and 30 control individuals. The serum levels of Ang-2 and VEGF of each patient were measured by ELISA prior to treatment. RESULTS & CONCLUSIONS: Serum levels of Ang-2 and VEGF are correlated (p < 0.0001). High serum levels of Ang-2 and VEGF isolated and both combined (high(Ang-2/VEGF)) correlate with likelihood of presenting NSCLC (p = 0.016; p = 0.003; p < 0.0001, respectively). Serum levels of Ang-2 and high(Ang-2/VEGF) but not VEGF alone are independent prognostic factors (p = 0.001; p = 0.619; p = 0.005). High(Ang-2/VEGF) serum levels could be exploited as a new valuable integral biomarker in NSCLC.

Topotecan in second-line treatment of small-cell lung cancer--how it works in our daily clinical practice?

Lung cancer is one of the most commonly diagnosed malignancies and it causes more than 1 million deaths each year worldwide. Small-cell lung cancer (SCLC) accounts for about 15 to 20% of all lung cancers and it is an extremely aggressive cancer, having a response rate of 60-80% with the standard first-line chemotherapy (CT). Topotecan is a topoisomerase I inhibitor currently approved for relapsed SCLC. The authors reviewed the clinical files of SCLC's patients (pts) of a single institution, the Portuguese Institute of Oncology-Porto Centre, in a five year period. The end-points were to evaluate response rates (RR), time to progression (TTP), overall survival (OS) and toxicity profile of topotecan as a second-line treatment of SCLC. From January of 2002 to December of 2006, it was diagnosed 146 pts with SCLC, 32 were submitted to second-line treatment and 23 with topotecan. The RR was 17.4%, median TTP and median survival after topotecan were 2.8 months and 6.3 months, respectively, and median OS was 17.5 months. The incidence of grade 3 and 4 adverse events was 16.6 and 2.6%, respectively. Topotecan showed clinical activity in our unselected daily patients with relapsed SCLC, with acceptable toxicity, in accordance with the published literature.