Cancer metastasis and elasticity of microenvironment

Cancer deaths are primarily caused by metastases, not by the parent tumor. During metastasis, malignant cells detach from the parent tumor, and spread through circulatory system to invade new tissues. Due to the intrinsic difficulties of predicting and monitoring in vivo metastasis, the physical-chemical mechanisms and parameters within the cellular microenvironment that initiate the onset of metastasis remain largely unknown (Chapter 1). Such a gap in the understanding and prediction of the onset of metastasis is of particular concern in colon cancer. We discovered that HCT-8 colon cancer cells can be induced to undergo a phenotypic transition similar to the early stage of metastasis (MLP, i.e. metastasis-like phenotype) simply by growing them on a substrate with appropriate mechanical stiffness (Chapter 2). This metastasis-like transition is observed as a change from a flattened, epithelial cell (E cell) to a rounded, dissociated cell morphology (R cell). We have carried out a comprehensive biophysical, biochemical and animal metastasis study to explore this E-R transition (Chapter 3). We found, R cells express a remarkable number of in vitro biophysical and biochemical metastasis hallmarks, such as loss of cell-cell adhesion and cell-substrate interaction, gain of anchorage-independence growth, decrease of cell elasticity, alteration of migration patterns in blood capillary, mimicking micro-channels and increase of stem cell markers expression (Chapter 4). RNAseq analyses indicate metastasis-enhancing gene expression pattern was activated in R cells. The results of both in vitro invasion assays and in vivo animal model metastasis experiments verified that R cells are significantly more invasive and tumorigenic than the original E cells that were never exposed to soft substrates (Chapter 5). Furthermore, we demonstrated additional cancer cell lines (SW480, HCT116 colon cancer cells and DU145 prostatic cancer cells) also exhibit a similar E-R transition following culture on the appropriate mechanical microenvironment. This in vitro model may provide unique opportunities to enable the dissection of not only the early mechanical and molecular events responsible for the ability of colon cancer cells to sense and respond their tumor mechanical microenvironment but also the downstream molecular mechanisms leading to the onset of metastasis (Chapter 6). We provided in-depth discussion and proposed a mechanosensing model to explain this E-to-R transition (Chapter 6). Our findings may also help to identify new molecular markers of the early stages of metastasis and for the design of anti-metastatic therapeutics. Apart from the major focus of this dissertation, i.e. an in vitro, mechanics-induced metastasis-like phenotype (MLP), we also investigated the influence of the mechanical microenvironment on cell behavior in three additional projects: (1) the investigation of whether cardiac cells can interact with one another mechanically, and if so, how does the interaction depend on cell-cell separation, and the stiffness of the medium (Chapter 7); (2) development of a simple, novel and general method to pattern a variety of cell adhesion molecules, i.e. Fibronectin (FN), Laminin (LN) and Collagen I (CN), etc. and living cells on PA gels (Chapter 8); and (3) development of a finite-element-method-based cell traction force microscopy (TFM) technique to estimate the traction forces produced by multiple isolated living cells as well as cell clusters (Chapter 9).

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Mechanical Engineering

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2014

Author dc:creator

• Tang, Xin

Contributors dc:contributor

• Saif, M. Taher A.
• Kuhlenschmidt, Mark S.
• Wang, Ning
• Hilgenfeldt, Sascha
• Katzenellenbogen, John A.

• Cancer metastasis
• Mechanosensing
• Mechanotransduction
• Nano-electro-mechanical systems (NEMS)
• Cardiac Mechanics
• Micro-patterning Techniques
• Cell Traction Force Microscopy
• Micro-electro-mechanical systems (MEMS)

Statement dc:rights

• Copyright 2013 Xin Tang

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/46930

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/46930