Bulletin of the American Physical Society
APS March Meeting 2011
Volume 56, Number 1
Monday–Friday, March 21–25, 2011; Dallas, Texas
Session H39: Focus Session: Physics of Cancer |
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Sponsoring Units: DBP Chair: Robert Austin, Princeton University Room: A124/127 |
Tuesday, March 22, 2011 8:00AM - 8:36AM |
H39.00001: Nanotechnology Approaches to Studying Epigenetic Changes in Cancer Invited Speaker: Placing polyelectrolytes into confined geometries has a profound effect on their molecular configuration. For instance, placing long DNA molecules into channels with a cross-section of about 100 nm$^2$ stretches them out to about 70\% of their contour length. We are using this effect to map epigenetic changes on single DNA and chromatin strands. This mapping on single molecules becomes central in the study of the heterogeneity of cell population in cancer, since rapid change of epigenetic makeup, propagated through rare cancer stem cells, is a hallmark of its progression. We demonstrate the basic building blocks for the single-molecule epigenetic analysis of genomic sized DNA. In particular, we have achieved the mapping of methylated regions in DNA with heterogeneous 5-methyl cytosine modification using a specific fluorescent marker. We further show that chromatin with an intact histone structure can be stretched similar to DNA, and that the epigenetic state of histone tails can be detected using fluorescent antibodies. [Preview Abstract] |
Tuesday, March 22, 2011 8:36AM - 8:48AM |
H39.00002: Cancer Evolution under Drug-Induced Stress-Gradients Guillaume Lambert, Robert H. Austin The lack of long term success in eliminating cancer cells while avoiding the evolution of drug resistance indicates that our understanding of how cells evolve in response to stress is still incomplete. We interpret this not as a failure of the current approaches, but rather as an indication that new research venues should be undertaken, where conventional wisdom is challenged in order to drive forward our understanding of cancer. Of particular importance, we believe that the powerful role of evolution in the origin of drug resistance is ill-understood. We do not ask whether evolution occurs, but rather how. We do not describe molecular mechanisms underlying drug resistance at the single cell level, but rather ask how does resistance spread in cancerous tissues and metastatic lesions. We attempt to answer these questions by studying the population-wide dynamics of drug evolution and the collective stress response of cancer cells in a microfluidics device. We use microfluidics technologies to impose high levels of stress on cancer cell metapopulation by create smoothly varying gradients of either oxygen, chemotherapeutic drug, nutrient or pH. We present long-term studies of the adaptation of tumorigenic cancer cells to drug- induced stress gradients. [Preview Abstract] |
Tuesday, March 22, 2011 8:48AM - 9:00AM |
H39.00003: Are biomechanical changes necessary for tumor progression? Josef A. Kas, Anatol Fritsch, Tobias Kiessling, David K. Nnetu, Steve Pawlizak, Franziska Wetzel, Mareike Zink With an increasing knowledge in tumor biology an overwhelming complexity becomes obvious which roots in the diversity of tumors and their heterogeneous molecular composition. Nevertheless in all solid tumors malignant neoplasia, i.e. uncontrolled growth, invasion of adjacent tissues, and metastasis, occurs. Physics sheds some new light on cancer by approaching this problem from a functional, materials perspective. Recent results indicate that all three pathomechanisms require changes in the active and passive cellular biomechanics. Malignant transformation causes cell softening for small deformations which correlates with an increased rate of proliferation and faster cell migration. The tumor cell's ability to strain harden permits tumor growth against a rigid tissue environment. A highly mechanosensitive, enhanced cell contractility is a prerequisite that tumor cells can cross its tumor boundaries and that this cells can migrate through the extracellular matrix. Insights into the biomechanical changes during tumor progression may lead to selective treatments by altering cell mechanics. Such drugs would not cure by killing cancer cells, but slow down tumor progression with only mild side effects and thus may be an option for older and frail patients. [Preview Abstract] |
Tuesday, March 22, 2011 9:00AM - 9:12AM |
H39.00004: A cellular automaton model for tumor growth in heterogeneous environment Yang Jiao, Sal Torquato Cancer is not a single disease: it exhibits heterogeneity on different spatial and temporal scales and strongly interacts with its host environment. Most mathematical modeling of malignant tumor growth has assumed a homogeneous host environment. We have developed a cellular automaton model for tumor growth that explicitly incorporates the structural heterogeneity of the host environment such as tumor stroma. We show that these structural heterogeneities have non-trivial effects on the tumor growth dynamics and prognosis. [Preview Abstract] |
Tuesday, March 22, 2011 9:12AM - 9:48AM |
H39.00005: Microfabricated Tepui: probing into cancer invasion, metastasis and evolution in a 3D environment Invited Speaker: Cancer metastasis and chemotherapeutic resistance are the major reasons why cancer remains recalcitrant to long-term therapy. We are interested to know: 1. How cancer cells invade tissues and metastasize in a 3D spatial environment? 2. How cancer cells evolve resistance to chemotherapeutic therapy? Answering these fundamental questions will require spatially propagating cancer cells in a 3D \textit{in vitro }micro environment with dynamically controlled chemical stress. Here we attempt to realize this micro environment with a three-dimentional topology on a micro-chip which consist of isolated highlands (Tepui) and deep lower lands. Cancer cells are patterned in the lower lands and their spatial invasion to the mesas of Tepui is observed continuously with a microscope. Experiments have demonstrated that the cell invasion potential is time dependent, which is not only determined by cell motility, but also cell number and spatial stress. Quantitative analysis shows that the invasion rate fits logistic equation. Further more, we have also imbedded collagen based Extracellular Matrix (ECM) inside these structures and established a robust chemical gradient in a vertical space. With merit of real-time confocal imaging, cell propagation, metastasis and evolution in the 3D environment are studied with time as a model for cell behavior inside tissues. [Preview Abstract] |
Tuesday, March 22, 2011 9:48AM - 10:00AM |
H39.00006: Study of breast cancer cell behavior under chemical stress using microfluidic gradient generator Amy Wu, Kevin Loutherback, Guillaume Lambert, Liyu Liu, Robert Austin, James Sturm Understanding the behavior of cancer cells in gradients of chemotherapeutic agents is important in studying the evolution of cancer drug resistance. Compared to traditional in-vitro methods, microfluidic gradient generators better control temporal and spatial profile of gradients. However, maintaining chemical gradients requires high flow rate of liquid (10ul/hr) in microfluidic chip while culturing mammalian cells demands slow flow rate of liquid (1ul/hr). In this paper, we modify a microfluidic gradient generator (Jeon et al, Langmuir, 2001) to overcome the challenge of maintaining slow flow rate and stable gradients simultaneously based on numerical simulations, and culture metastatic breast cancer cell line (MDA-MB-231) in the chip. To characterize the stability of gradients, we visualize the gradient profile by infusing fluorescein. Finally, we will report the response of the on-chip culture under the stress of chemical gradients, observing for cellular phenotypic changes including death, proliferation, morphology, and migration. [Preview Abstract] |
Tuesday, March 22, 2011 10:00AM - 10:12AM |
H39.00007: Superficial dose distribution in breast for tangential radiation treatment of breast cancer Roumiana Chakarova, Magnus Gustafsson, Anna Baeck, Ninni Drugge, Asa Palm, Andreas Lindberg, Mattias Berglund The superficial (0-2 cm) dose distribution in a cylindrical phantom is examined theoretically and experimentally when irradiated by tangential photon beams. The lateral superficial part of the phantom is shown to receive full dose beyond 2 mm whereas the build-up region is up to 7 mm where the beams enter. Eclipse AAA calculations agree well with the experimental and Monte Carlo data while Eclipse PBC underestimates the entrance dose the first 3-4 mm and fails to give a correct lateral dose close to the surface up to 10 mm depth. The performance of the Eclipse algorithms is evaluated in a number of clinical cases with Monte Carlo results. Examples are given to illustrate how differences in geometrical presentation of the body structure in the treatment planning system and the Monte Carlo simulation as well as the patient voxelization may affect the evaluation results. [Preview Abstract] |
Tuesday, March 22, 2011 10:12AM - 10:24AM |
H39.00008: Origin of using cisplatin over transplatin for cancer treatment: An ab initio study Sa Li, Puru Jena Eventhough cisplatin has been used as a chemotherapy anti-cancer drug for over 40 years the thermodynamics and kinetics of the reactions are still largely unknown. Cisplatin molecules are known to be attacked by water molecules before they react with DNA. As a result, two Cl atoms are eliminated. The active piece in the cell, therefore, is not cisplatin but (NH$_{3})_{2}$Pt$^{2+}$. To explain why only cisplatin but not transplatin functions as anticancer drug, we used first principles method to study the dechlorination process in cis- and transplatin. Although transplatin molecule is more stable than cisplatin by 0.52 eV, we found cisplatin to be more favorable for reaction due to the following reasons: 1) the energy cost to remove a Cl atom is less from cisplatin than transplatin. 2) cis-form (NH$_{3})_{2}$Pt$^{2+}$ derived from cisplatin with N-Pt-N angle of 97\r{ } is lower in energy than trans-form derived from transplatin with N-Pt-N angle of 180\r{ }. The rotation barrier for N-Pt-N changing from 180\r{ } to 97\r{ } is about 1.0 eV. 3) When cis-form of (NH$_{3})_{2}$Pt$^{2+}$ reacts with two Guanines in DNA, the two N atoms in Guanines can readily bind to the Pt atom in cisplatin. The transplatin due to steric reasons does not provide that opportunity. [Preview Abstract] |
Tuesday, March 22, 2011 10:24AM - 10:36AM |
H39.00009: Actinomycin D binding mode reveals the basis for its potent HIV-1 and cancer activity Thayaparan Paramanathan, Ioana D. Vladescu, Micah J. McCauley, Ioulia Rouzina, Mark C. Williams Actinomycin D (ActD) is one of the most studied antibiotics, which has been used as an anti-cancer agent and also shown to inhibit HIV reverse transcription. Initial studies with ActD established that it intercalates double stranded DNA (dsDNA). However, recent studies have shown that ActD binds with even higher affinity to single stranded DNA (ssDNA). In our studies we use optical tweezers to stretch and hold single dsDNA molecule at constant force in the presence of varying ActD concentrations until the binding reaches equilibrium. The change in dsDNA length upon ActD binding measured as a function of time yields the rate of binding in addition to the equilibrium lengthening of DNA. The results suggest extremely slow kinetics, on the order of several minutes and 0.52 $\pm $ 0.06 $\mu $M binding affinity. Holding DNA at constant force while stretching and relaxing suggests that ActD binds to two single strands that are close to each other rather than to pure dsDNA or ssDNA. This suggests that biological activity of ActD that contributes towards the inhibition of cellular replication is due to its ability to bind at DNA bubbles during RNA transcription, thereby stalling the transcription process. [Preview Abstract] |
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