Abstract
Abstract A crucial point in making treatment decisions for cancer patients is the assessment of tumor aggressiveness. Currently, for breast cancer, established prognostic markers exist that are routinely assessed by standard pathological examination. However, these parameters are often not sufficient to stratify patients, especially those with early stages of breast cancer and adjuvant therapy is frequently administered to patients who might have been cured by surgery and anti-hormonal treatment alone. The goal to avoid over- and under-treatment has led to an intensive search for prognostic and predictive markers in early breast cancer. Physical interactions between cancer cells and the extracellular matrix (ECM) that occur at the molecular (nanometer) scale are crucial for the metastatic process. Consequently, nanomechanical alterations of cells and ECM due to cancer progression can serves as potentially suitable markers of cancer aggressiveness that may help to optimize treatment strategies. This motivated us to develop an atomic force microscope (AFM)-based method for measuring nanomechanical (stiffness) profiles of unadulterated tissues in native physiological buffer conditions with an unprecedented stiffness sensitivity resolved at nanometer-scale spatial resolution. An AFM utilizes a ∼10 nm-sharp stylus or tip that makes ∼10’000 miniscule indentations across tissue. In our initial study using transgenic mouse model of human breast cancer we could show that the “softest” nanomechanical phenotype (∼0.4 - 0.8 kPa) present at the primary tumor site closely corresponded to the stiffness of the metastatic lesions obtained from the lungs of the same mouse (Plodinec et. al; Nature Nanotech. 2012). In this study, we have analyzed human 187 breast cancer samples from breast biopsies and tumor resections including primary breast cancers of various stage and grade, lymph node metastases, and non-neoplastic breast parenchyma. Post-AFM samples were fixed, paraffin embedded in an oriented manner and used for routine histology. Data showed for all human breast cancer samples, distinct stiffness phenotypes in comparison to the surrounding non-neoplastic and morphologically normal breast tissue and revealed specific nanomechanical profiles of phenotypes that lead to metastases. Interestingly, patients presenting nanomechanical changes in the adjacent tissue, which was histologically characterized as tumor free, typically exhibited local and/or distant metastases. Overall, our findings demonstrate the first application of nanomechanical profiling in a clinical setting that allows for fast, on-site assessment of specimen and does not suffer from inter-observer variability such as other markers (Obermann et al, Pathologe, 2012). The relative size and distribution of nanomechanical profiles can provide an indicator of cancer aggressiveness, and therefore orientate therapy choice, and support patient follow-up. Citation Format: Marija Plodinec, Christian Raez, Philipp Oertle, Adrian Hodel, Maja Fünfschilling, Roderick YH Lim, Ellen C. Obermann. Nanomechanical profiling of breast cancer: A novel tool for cancer diagnostics and prognostics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3926.
Published Version
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