Mechanical cell-substrate feedback explains pairwise and collective endothelial cell behavior in vitro

René F.M. van Oers, +Roeland Merks 

In vitro cultures of endothelial cells are a widely used model system of the collective behavior of endothelial cells during vasculogenesis and angiogenesis. When seeded in a extracellular matrix, endothelial cells can form blood vessel-like structures, including vascular networks and sprouts. Endothelial morphogenesis depends on a large number of chemical and mechanical factors, including the compliancy of the extracellular matrix, the available growth factors, the adhesion of cells to the extracellular matrix, cell-cell signaling, etc. Although various computational models have been proposed to explain the role of each of these biochemical and biomechanical effects, the mechanisms underlying in vitro angiogenesis are still poorly understood. Most explanations focus on predicting the whole vascular network or sprout from the underlying cell behavior, and ignore the intermediate organizational levels of the system. Here we show, using a hybrid Cellular Potts and finite-element computational model, that a single set of biologically plausible rules describing (a) the contractile forces that endothelial cells exert on the ECM, (b) the resulting strains in the extracellular matrix, and (c) the cellular response to the strains, suffices for reproducing the behavior of individual endothelial cells and the interactions of endothelial cell pairs in compliant matrices. With the same set of rules, the model also reproduces network formation and sprouting from epithelial spheroids. Combining the present, mechanical model with aspects of previously proposed mechanical and chemical models may lead to a more complete understanding of in vitro angiogenesis.

Arxiv: [PDF] 

The Cancer Diaspora: Metastasis beyond the seed and soil hypothesis

Kenneth J. Pienta, Bruce Robertson, Donald S. Coffey, Russell S. Taichman

(Submitted on 8 Aug 2013)

Do cancer cells escape their confinement of their original habitat in the primary tumor or are they forced out by ecological changes in their home niche? Describing metastasis in terms of a simple one-way migration of cells from the primary to target organs is an insufficient concept to cover the nuances of cancer spread. A diaspora is the scattering of people away from an established homeland. To date, diaspora has been a uniquely human term utilized by social scientists, however, the application of the diaspora concept to metastasis may yield new biological insights as well as therapeutic paradigms. The diaspora paradigm takes into account and models several variables: the quality of the primary tumor microenvironment, the fitness of individual cancer cell migrants as well as migrant populations, the rate of bidirectional migration of cancer and host cells between cancer sites, and the quality of the target microenvironments to establish metastatic sites. Ecological scientific principles can be applied to the cancer diaspora to develop new therapeutic strategies. For example, ecological traps, habitats that lead to the extinction of a species, can be developed to attract cancer cells to a place where they can be better exposed to treatments or to cells of the immune system for improved antigen presentation. Merging the social science concept of diaspora with ecological and population sciences concepts can inform the cancer field to understand the biology of tumorigenesis and metastasis and inspire new ideas for therapy.

http://arxiv.org/abs/1308.1938

Spatial evolution of tumors with successive driver mutations

Tibor Antal, P. L. Krapivsky, M. A. Nowak

(Submitted on 7 Aug 2013)

We study the spatial evolutionary dynamics of solid tumors as they obtain additional driver mutations. We start with a cancer clone that expands uniformly in three dimensions giving rise to a spherical shape. We assume that cell division occurs on the surface of the growing tumor. Each cell division has a chance to give rise to a mutation that activates an additional driver gene. The resulting clone has an enhanced growth rate, which generates a local ensemble of faster growing cells, thereby distorting the spherical shape of the tumor. We derive analytic formulas for the geometric boundary that separates the original cancer clone from the new mutant as well as the expanding frontier of the new mutant. The total number of original cancer cells converges to a constant as time goes to infinity, because this clone becomes enveloped by mutants. We derive formulas for the abundance and diversity of additional driver mutations as function of time. Our model is semi-deterministic: the spatial growth of the various cancer clones follows deterministic equations, but the arrival of a new mutant is a stochastic event.

http://arxiv.org/abs/1308.1564

Reduction of Breast Cancer Relapses with Perioperative Non-Steroidal Anti-Inflammatory Drugs: New Findings and a Review

Reduction of Breast Cancer Relapses with Perioperative Non-Steroidal 
Anti-Inflammatory Drugs: New Findings and a Review 

Michael Retsky, Romano Demicheli, William JM Hrushesky, Patrice Forget, Marc De Kock, Isaac Gukas, Rick A Rogers, Michael Baum, Vikas Sukhatme and Jayant S Vaidya

Abstract: To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients identified in multiple databases, we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. However in order to explain early relapses, we had to postulate that something happens at about the time of surgery to provoke sudden exits from dormant phases to active growth
and then to detection. Most relapses in breast cancer are in the early category. Recent data from Forget et al. suggests an unexpected mechanism. They retrospectively studied results from 327 consecutive breast cancer patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Relapse hazard updated Sept 2011 are presented. A common Non-Steroidal Anti-Inflammatory Drug (NSAID) analgesic used in surgery produced far superior disease-free survival in the first 5 years
after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Transient systemic inflammation accompanying surgery could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent.

While this paper is not currently available on a server, the author is happy to provide them to interested parties.  If interested, contact Michael Retsky at:
michael.retsky@gmail.com