Geoffrey West, Santa Fe Institute

Physics Talk Background Papers:

A quantitative theory of solid tumor growth and vascularization

Supplimental Material

Don Ingber, Harvard

Central Question & Paper:

• What properties of the embryonic micromenviroment convey its ability to induce cancer differentiation?

Robert Getzenberg (JHU) & Don Coffey (JHU) : Additional Material

These three articles will flow towards the metastatic aspects of the concepts in our discussions. 

 

We understand that Dr. Michor is attending the meeting but wanted to include one of the papers on which she is an author since it raises what we feel is a very important concept.  This manuscript on quasispecies connects chromosome structure to evolution and cancer and introduces some mathematical issues.  The recent paper on pattern recognition will provide a link to the physics on this topic. We are sure that Herb Levine will apply his vast experience to this problem.  The last of the papers is an old review on the tissue matrix that sets the background for the structural aspects of what we will discuss. 

Background Papers:

• Reaction-Diffusion Model as a Framework for Understanding Biological Pattern Formation
• Genetic instability and the quasispecies model
• The Tissue Matrix: Cell Dynamics and Hormone Action

Chuck Drake, Johns Hopkins University

Three Problems:

• Do cancer cells metastasize as single cells, as clusters of tumor cells, as clusters of tumor and myeloid cells, or as fusions between tumor cells and macrophages?
• What is the relative role of passive (fluid dynamic) versus active processes (diapedesis, extravascation) in the establishment of metastases from tumor cells circulating in the vascular or lymphatic compartments?
• At what stage in the metastatic process are tumor cells most susceptible to immunological intervention? 

Background Papers:

• Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed?
• Integrins in cancer: biological implications and therapeutic opportunities
• Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis
• Circulating Tumor Cell Clusters in the Peripheral Blood of Colorectal Cancer Patients

Robert Vessella, University of Washington

Key Challenge:

• Development of the technologies that will allow us to isolate viable single metastatic cells and then interrogate those individual cells for molecular signatures and biological behavior.   This remains a huge challenge especially in the study of dormancy.

Background Papers:

• Extracellular matrix: A gatekeeper in the transition from dormancy to metastatic growth 
• Tumor Dormancy and Metastasis

Scott Guelcher, Vanderbilt

Three Questions:

• What characteristics unique to the bone microenvironment induce tumor cells to express osteolytic factors after the tumor becomes established in bone?
• Over what range of tissue-level mechanical properties can tumor cells respond to the rigidity of the microenvironment?
• Are tumor cells genetically programmed to metastasize to bone or are they attracted to the unique characteristics of the bone microenvironment?

Background Papers:

• Inhibition of Rho-Associated Kinase Signaling Prevents Breast Cancer Metastasis to Human Bone
• Matrix Rigidity Induces Osteolytic Gene Expression of Metastatic Breast Cancer Cells
• Extracellular Matrix Rigidity Promotes Invadopodia Activity

Chris Contag, Stanford

Three Problems:

• The small numbers of cells that comprise early metastatic sites make these sites difficult to locate.
• The nature of metastatic cells is uncertain without clear cell surface markers or other known distinguishing characteristics, and therefore identifying those cells is difficult. Using cell surface markers that are characteristic of late stage disease may not be relevant.
• The characteristics of a cancer cell the enable it to escape the primary site are not well understood and the markers on such cells have not been described.

Background Papers:

• Synergistic Antitumor Effects of Immune Cell-Viral Biotherapy

• Integrating the biological characteristics of oncolytic viruses and immune cells can optimize therapeutic benefits of cell-based delivery

• Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models.

Lalit Patel, University of Michigan

The progression of prostate cancer is believed to occur in sequential steps. A primary tumor forms, becomes aggressive, disseminates aggressive cells that invade a secondary site, forms a metastasis, the metastases metastasize, and a lethal phenotype emerges. Empirical findings challenge this linear view of disease progression. It has been demonstrated that prostate cancer disseminates to and invades the bone marrow of patients who present with organ-confined early stage primary disease. Although these cells (DTCs) are present at prostatectomy - biochemical evidence of disseminated disease does not present for several years and the cells themselves lack proliferation markers. These findings suggest a latent-phase in which the majority of Homo sapien bone disseminated prostate cancer cells lack metastatic potential. This raises the following questions:

1) Metastogenesis by DTCs:

• Are bone metastases in Homo sapiens the slow expansion of rare non-dormant clones or is there a time delayed recurrent secondary-site specific "metastogenic-transformation" that activates skeletal tumor formation by DTCs?

2) Heterogeneity of DTCs:

• how many molecular-phenotypes of dormancy are there amongst Homo sapien prostate cancer DTCs?
• how many dormancy escape mechanisms are there?
• are dormancy escape mechanisms redundant, convergent, or divergent?
• is the escape route from dormancy ultimately taken by DTCs predestined by clonal origins or selected for by recurrent secondary transformations at the metastatic site?

3) Seed-Soil relationship of DTC dormancy and the bone microenvironment:

• is dormancy a byproduct of selection for dormant clones by the metastatic process?
• is dormancy induced by the bone marrow microenvironment/metastatic niche?
• what microenvironmental cues (molecular, structural, or mechanical) would confer/ablate tumor cell dormancy?
• can dormant DTCs “prime-the-soil” through microenvironmental manipulation for future tumor formation?

Suggested Readings:

• Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009 Apr;9(4):302-12.
• Holcomb IN, Grove DI, Kinnunen M, Friedman CL, Gallaher IS, Morgan TM, Sather CL, Delrow JJ, Nelson PS, Lange PH, Ellis WJ, True LD, Young JM, Hsu L, Trask BJ, Vessella RL. Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate cancer patients. Cancer Res. 2008 Jul 15;68(14):5599-608.
• Psaila B, Kaplan RN, Port ER, Lyden D. Priming the 'soil' for breast cancer metastasis: the pre-metastatic niche. Breast Dis. 2006-2007;26:65-74.