Biochemistry and Molecular Biology
Penn State Science
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Andrea Mastro

Andrea Mastro

Main Content

  • Professor of Microbiology and Cell Biology
428 South Frear Laboratory
University Park, PA 16802
Email: a36@psu.edu
Phone: (814) 863-0152

Research Interests

Breast cancer and immune system

Graduate Programs

BMMBMCIBSPH

Research Summary

The Interaction of Metastatic Breast Cancer Cells with Osteoblasts

Breast cancer cells frequently metastasize to the skeleton where they grow and cause bone loss.  The cancer cells do not themselves destroy the bone but disturb the balance of  the normal bone remodeling cells, osteoblasts and osteoclasts.  We have focused on the intereactions of metastatic cancer cells with osteoblasts.  We have used three different models, cell culture, a three-dimensional bioreactor, and animals to study this cell-cell interactions. We have found both in vitro and in vivo that the cancer cells cause increased osteoblast apoptosis, reduced production of matrix proteins, and increased production of a set of inflammatory cytokines, IL-6, IL-8, MCP-1, and VEGF. These same cytokines have been seen as part of an osteoblast stress response in other diseases. They are known to attract and activate osteoclasts, the cells that degrade the bone matrix.  We currently are studying the control of transcription of these cytokines through NFκB and signal transducing molecules.  We are examining their expression in bone early in the metastatic process.  Finally, we are trying to mimic the bone environment in vitro by addition of osteoclasts to the three- dimensional osteoblast culture system. In this bioreactor model we have visualized cancer cells form single cell files and causing morphological changes in the osteoblastic tissue. These properties are not seen in standard tissue culture but are seen in pathological tissue. Pre-osteoclasts also differentiate into active osteoclasts in the bioreactor and bring about a loss of osteoblastic matrix.  These three approaches will permit us to tease apart various aspects of the bone metastatic environment.

Exercise, diet and the immune system
For some time we have been interested in the cells of the immune system as influenced by exercise. In one study we followed the blood lymphocyte population of women following breast cancer chemotherapy.  In another we examined the iron status of the elderly.  In a current study we are examining the blood cells following high protein diets of several types and how exercise affects the lymphocyte subpopulations.  In all of these, it is clear that diet and exercise are integral components of the immune system.

 

Mastro figure 1

Figure 1. A, osteogenic tissue maturation in the bioreactor recapitulates development of native bone by systematic and reproducible phenotypic maturation of preosteoblasts through mineralizing osteoblasts to terminally differentiated osteocytes. B, MC3T3-E1 cells produce and mineralize a thick, engulfing extracellular matrix (ECM) that slowly decreases in thickness and number of cell layers through progressive apoptosis to a final stable state exhibiting no sign of tissue necrosis over 10 months of continuous culture (graph). C-F, interaction of MDA-MB-231GFP human cancer cells (green, GFP) with osteogenic tissue (red, osteoblasts; black, ECM) depends on tissue maturity (B, table) and exhibits stages of cancer cell adhesion (C), penetration (D), and alignment of cancer cell into files (E) that are reminiscent of events observed in pathologic tissue. F, filing is especially evident in corresponding 3D confocal reconstructions. G-I, for comparison, Indian Filing is shown in a section from bone (solid pink) with metastatic breast cancer (rows of cells with dark purple nuclei). The scale bars in A, C, and D represent 50 μm, the scale bar in F represents 100 μm, the scale bar in G represents 200 μm, and the scale bars in H and I represent 50 μm.



 

Mastro figure 2


Figure 2: Murine MCP-1, IL-6, and VEGF are Localized in the Bone Microenvironment
Femurs were  harvested from athymic nude mice inoculated with metastatic breast cancer cells were cryosectioned in 10 µm thick longitudinal sections, and stained for murine VEGF, murine MCP-1, or murine IL-6 via immunohistochemistry, and visualized using a brown DAB chromogen stain.  Slides were counterstained using Gill’s Hematoxylin.  a,c) Murine VEGF and b,d) murine MCP-1 were localized in trabecular bone of the proximal and distal femur.  e,g)  urine VEGF and f,h) murine MCP-1 were localized in cortical bone of the proximal and distal metaphyses.  Neither i) murine MCP-1 nor j) murine VEGF were localized in cortical bone of the diaphysis.  k) Murine IL-6 was localized throughout the bone marrow.  Murine IL-6 was not present in the trabecular bone or the cortical bone matrix.  At least three independent sections were stained per bone, and three bones examined per un-inoculated or inoculated MDA-MB-231-

Selected Publications

  • Molls, Roshni R., N. Ahluwalia, A.M. Mastro, H. Smiciklas-Wright and G.C. Handte.  2005.  Nutritional status predicts primary subclasses of T cells and lymphocyte proliferation response in healthy older women. Journal of Nutrition 135: 2644-2650.
  • Phadke, P.A., R.R. Mercer, J.F. Harms, Y. Jia, J.C. Kappes, A.R. Frost, J.L. Jewell, K.M. Bussard, S. Nelson, C. Moore, C.V. Gay, A.M. Mastro and D.R. Welch. 2006. Kinetics of metastatic breast cancer cell trafficking in bone. Clin. Canc. Res., 12: 1431-1440.
  • Bush, J.S., A.M. Mastro, and W. J. Kraemer. 2006. Proenkephalin peptide F immunoreactivity in different circulatory biocompartments. 2006. Peptides 27: 1498-1506.
  • Dhurjati R., Liu X., Gay C.V., A.M. Mastro and Vogler E.A. Extended-Term Culture of Bone Cells in a Compartmentalized Bioreactor. 2006. Tissue Engineering. 12: 3045-3054
  • Kraemer, W.J., Nindl, B.C., Marx, J.O., Gotshalk, L.A., Bush, J.A., Welsch. J.R., Volek, J.S., Spoering, B.A., Maresh, C.M., Mastro, A.M., and Hymer.  W.C. 2006. Chronic resistance in women potentiates growth hormone in vivo bioactivity: characterization of molecular mass variants. Am. J. Physiol. Endocrinal Metabolism, 291: E1177-1187.
  • Tittmann, Berhnard R., Miyasaka, Chiaki, Mastro, A. M., Mercer, Robyn R.  2007.  Study of Cellular Adhesion with Scanning Acoustic Microscopy.  IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control.  54: 1502-1513.
  • Liu, X, Lim, J.Y., Donahue, H.J., Dhurjati, R., Mastro, A.M., Vogler, E.A.  2007. Influence of Substratum surface chemistry/energy and topography of the human fetal osteoblastic cell line hFOB 1.19: Phenotypic and genotypic responses observed in vitro.  Biomaterials 28:4535-4550.
  • Bussard, K.M., C.V. Gay, and A.M. Mastro. 2008.  The Bone Microenvironment in Metastasis:  What Is Special About Bone?  Cancer Metastasis Reviews 27:41-55.
  • Kraemer, W.J., Nindl, B.C., Volek, J.S., Marx, J.O., Gotshalk, L.A. Bush, J.A., Welsch, J.R., Vingren, J.L.,  Spiering, B.A., Fragala, M.S., Hatfield, D.L., Ho, J.Y., Maresh, C.M., A.M. Mastro, Hymer, W.C.  2008.  Influence of oral contraceptive use on growth hormone in vivo bioactivity following resistance exercise:  Responses of molecular mass variants. Growth Hormone & IGF Research 18: 238-244. 
  • Kinder, E. Chislock, K.M. Bussard, L. Shuman, and A.M. Mastro.  2008.  Metastatic breast cancer induces an osteoblast inflammatory response.  Exp Cell Res 314: 173-183.
  • Dhurjati, R,  Krishnan,, V L. A. Shuman, A. M. Mastro, E. A. Vogler. 2008. Metastatic breast cancer cell colonization degrades three-dimensional osteoblastic tissue in vito. Clin Exp Met  25:741-752
  • Welch DR, C. R. Cooper, D. R. Hurst, C. C. Lynch, M. D. Martin, K. S. Vaidya, M. N. VanSaun , A.M. Mastro. 2008 Metastasis Research Society-American Association For Cancer Research Joint Conference on Metastasis. Cancer Research. 68:9578-82.
  • Mastro, A.M., E. A. Vogler. 2009. A 3D Osteogenic-Tissue Model for the Study of Metastatic Tumor-Cell Interactions with Bone. Cancer Research, 69:4097-4100.
  • Chen, Y., D. Sosnoski, L. Novinger, U. H. Gandhi, K.S. Prabhu, A.M. Mastro. 2009 Selenium Modifies the Osteoblast Inflammatory Stress Response to Bone Metastatic Breast Cancer. Carcinogenesis.  Nov;30(11):1941-8. Epub 2009 Sep 16..
  • Krishnan, V., R. Dhurjati, E.A. Vogler, A.M. Mastro.  2009 Osteogenesis In Vitro: From Pre-Osteoblasts to Osteocytes. In Vitro Cell Dev Biol Anim. 2010 Jan;46(1):28-35. , (Epub Oct 14 Ahead of print).
  • Bussard, K. M. Mastro, A. M. 2009. Ex-vivo Analysis of the Bone Microenvironment in Bone Metastatic Breast Cancer. J Mammary Gland Biol Biol Neoplasia. Dec;14(4):387-95. Epub 2009 Dec 2. PMID 19949843
  • Bussard, K.M, N. Okita, N. Sharkey, T. Neuberger, A., Webb, A.M. Mastro. 2010. Localization of osteoblast inflammatory cytokines MCP-1 and VEGF to the matrix of the trabecula of the femur, a target area for metastatic breast cancer cell colonization. Clin Exp Metastasis 27:331-340.
  • Bussard, K.M., D.J. Venzon and A.M. Mastro.  2010. Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer. Journal of Biochemistry. In Press.