Prognostic and predictive significance of the cancer stem cell markers in lung and breast cancers

Abstract

Lung and breast cancers are the leading causes of cancer related mortalities in Australia and worldwide, resulting in around 35% of cancer deaths. Significantly, high proportion of patients treated with curative intent, relapse and eventually die of their cancer. The ability of cancers to recur despite definite local or systemic therapies suggest that minimal residual disease contains a population of cells with stem cell-like properties. Cancer Stem Cells (CSCs) are believed to be phenotypically distinct population of cells that possess enormous capacity of self-renewal and regeneration. Initially reported in haematological malignancies, and subsequently in several solid tumours, CSCs are potential therapeutic targets and several strategies are already in development. The current gold standard assay to study the tumorigenic potential of CSCs is their potential to grow in vivo as serially transplanted tumours in immunodeficient hosts, but the evidence in the clinical settings is limited. Several reports have shown that surface markers CD133, CD44 and cytosolic enzyme ALDH accurately identify cancer stem cell- like cells in human lung cancer, while ALDH and CD44+/CD24- phenotypes are more specific for breast cancer stem cells. If the cancer stem cell hypothesis is true, then the existence of marker positive cancer cells in tumour specimens should be associated with tumour recurrence, treatment resistance and poor survival. Conversely, therapeutic strategies targeted against these markers could potentially result in eradication these stem-like population and hence improvement in clinical outcome. The aim of the first study was to investigate the prognostic significance of putative CSC markers (CD133 and ALDH1A1) in patients with resected stage 1 NSCLC. The hypothesis was that the tumours with positive expression of putative CSC markers should be associated with tumour recurrence and poor survival after curative resection. Archived tumour specimens for selected patients were retrieved. Tumour specimens of 205 eligible patients were stained for CD133 and ALDH1A1 using immunohistochemistry with well-characterised primary antibodies. Expression was scored quantitatively in a blinded fashion and correlation of marker expression and clinical outcomes was performed using standard statistical tests. Subjects with CD133 and ALDH1A1 positive tumours had higher relapse rates and poor survival. The aim of the second study was to investigate the predictive role of ALDH1 in locally advanced breast cancer, treated with neo-adjuvant chemotherapy. The hypothesis was that tumour with high expression of ALDH1 should show poor pathological response to the chemotherapy. Tumour samples form 119 patients were serially obtained before, during and at the end of chemotherapy and immunohistochemically stained for ALDH1. Patients with ALDH1 positive tumours at baseline had poor response the chemotherapy and ALDH1 positive residual tumours at the end of chemotherapy, strongly predicted poor clinical outcome. The aim of the third study was to obtain clinical evidence to targeting CD44 expressing cancer stem-like cells in small cell lung cancer by using hyaluronic acid (HA) as an excipient. Results from 37 patients, suggest that the HA-irinotecan is safe in patients with small cell lung cancer and CD44v6 may be a novel therapeutic target.