Breast cancer, the most common cancer in women worldwide, claimed more than 500,000 deaths in 2012. 90% of those deaths happened because the cancer spread to different organs in the body, i.e. it metastasized. Effective lab bench models that mimic the events leading to metastasis within the body are needed urgently to better understand the process of metastasis and to identify drugs to treat it.
A study led by Kaushik Chatterjee and Annapoorni Rangarajan at the Indian Institute of Science (IISc) Bangalore, has demonstrated a three-dimensional (3D) porous scaffold that can closely mimic the environment that cancer cells encounter within the body. It can thus reveal how cancer cells really behave inside our body.
As a more robust platform that mimics human cancer in the lab, such 3D scaffolds could help to accelerate drug discovery and testing. Such technologies could minimize the need for animal testing; aside from being more humane it also overcomes limitations associated with the differences in human and animal physiology.
This novel model system overcomes many limitations of the most common model systems used by cancer biologists worldwide to study breast cancer progression. The two most common model systems are (a) growing breast cancer cells on plates made up of glass or plastic (in vitro) in a flat two-dimensional (2D) format, and (b) by injecting breast cancer cells in mice (in vivo) and tracking how cancer grows and spreads.
“But both these systems have limitations – 2D growth on glass or plastic is very different from in vivo tumor growth, whereas in vivo mouse models are both expensive and time-consuming.”, said Chatterjee, an expert in applying advanced materials technologies to study biomedical challenges.
It is well-established now that cancer is much more than just being a disease of a cell. It is affected by its surroundings in ways we are just starting to understand. “Previous studies have also developed 3D models, but the materials they used do not recapitulate the mechanical properties of the in vivo tumor environment.”, said lead author Gowri Balachander. “Therefore, we began to investigate what synthetic biocompatible polymers can be used to reconstitute the in vivo mechanical environment”.
Cells that were grown in these scaffolds were found to be more invasive and formed bigger tumors when introduced into mice as compared to those grown on 2D plastic plates. These cells had higher levels of the genes that play a crucial role in all three major steps of metastasis – initiation, progression, and colonization (settling down at a distant organ and starting a new tumor). Furthermore, these cells showed elevated expression of stemness genes. “The cancer stem cell properties play a major role in self-renewal and initiation of new tumors” said co-author Sai Balaji.
“Cells grown in our 3D porous scaffold are more metastatic when injected into mice than the ones grown on 2D plastic, suggesting that most of us had been underestimating the metastatic power of cancer cells by assuming 2D plastic to be a reliable replica of what actually goes inside the body”, said Rangarajan.
Cancer metastasizes mostly via our blood circulatory system. It enters the bloodstream, circulates, then exits into many different organs, and starts developing tumors there. This is a highly challenging process for the cancer cells. Only 0.01% of them eventually are able to start a new tumor or metastasis, yet metastasis kills more than 90% of patients, suggesting the cells that eventually metastasize must be very efficient.
“Therefore, we need to catch these cells in the process; for doing that, we need to accurately identify cellular signaling players they use. The genetic profiles of cells grown in our 3D scaffolds tell us that they were more involved in cell-cell interactions, more efficient at invading the non-cancerous tissue around them to probably reach the blood vessels, dividing quickly to support tumor growth, and creating situations similar to those when our tissue is inflamed. All these actions only fuel metastasis.”, said Balachander.
“Thanks to the recently established Center for Biosystems Science and Engineering (CBSSE). It provides a great inter-disciplinary platform to bring together scientists from different fields and integrate their expertise to tackle challenges such as cancer metastasis”, added Chatterjee.
About the authors
Kaushik Chatterjee is an Assistant Professor at the Department of Materials Engineering at IISc. Annapoorani Rangarajan is an expert in breast cancer stem cell biology and an Associate Professor at the Department of Molecular Reproduction, Development and Genetics at IISc.
Gowri M. Balachander is a PhD student at the recently established Center for Biosystems Science and Engineering (CBSSE) at IISc and co-advised by Drs Rangarajan and Chatterjee. Sai A Balaji is a co-author on the study, and a graduate student with Dr. Rangarajan.