Imaging of Novel Stem Cell Therapy Targeting Breast Cancer

Institution: Stanford University
Investigator(s): Joseph Wu, M.D., Ph.D. -
Award Cycle: 2008 (Cycle 14) Grant #: 14IB-0039 Award: $239,213
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2008)

Despite surgical removal of the primary breast tumor in patients with localized disease, relapse at local or distant sites may occur because of the presence of micro-metastases that are undetectable at the time of diagnosis. The development of new cytotoxic agents and radiation therapy techniques, administered as adjuvant therapy after surgery, has improved patient survival. However, adjuvant therapy is limited by discomforting side effects and a relapse rate of 20-40%. Given these serious drawbacks, it is important to develop novel approaches for the treatment of breast cancer.

Our interest in using stem cells as biological “search and destroy” vehicles came from recent findings showing that mesenchymal stem cells can home to breast tumors. However, in general adult stem cells have limited capacity for self-renewal, which can restrict clinical application at a large scale. By contrast, embryonic stem cells are capable of unlimited self-renewal and differentiation into all cell types within the body, including adult stem cells. For these reasons, we hypothesize that human embryonic stem cells, when properly characterized and tested, can lead to major breakthroughs in the treatment of breast cancer.

The proposal is divided into two aims. In Aim 1, we will differentiate human embryonic stem cells into natural killer cells (hESC-NKs) and endothelial cells (hESC-ECs). The natural killer cells can search and destroy local and metastasized breast cancer cells. The endothelial cells can home into breast tumors, incorporate into their vasculature, and later activated to undergo programmed cell death, thereby starving the breast tumors of essential nutrients and oxygen. In Aim 2, we seek to understand the underlying molecular mechanism by which hESC-NKs and hESC-ECs can home in to the breast tumors. We will use custom-designed antibody array that probes for >500 cytokines (signaling proteins regulating immune responses) simultaneously. The identification of specific cytokines released within the breast tumor microenvironment to attract circulating stem cells is a promising approach for determining the temporal kinetics of cytokine activation in relation to growth of tumors.




Final Report (2010)

Breast cancer is the most common cancer in women, with more than one million cases and 600,000 deaths occurring worldwide annually. In the US, breast cancer accounts for about 30% of all cancers diagnosed. The development of new cytotoxic agents and radiation therapy techniques, administered as adjuvant therapy after surgery, has improved patient survival. However, adjuvant therapy is disadvantaged by discomforting side effects and a relapse rate of 20-40%. Given these serious drawbacks, it is important to develop novel “out of the box” approaches for the treatment of breast cancer.

Our laboratory has gained significant expertise in the cultivation, differentiation, and transplantation of human embryonic stem cell (ESCs). For the CBCRP-funded IDEA project, we initiated development of a stem cell-based therapy to target both angiogenesis and breast tumors. Our two major aims are as follow:
(1) Isolate and characterize human ESC-derived endothelial cells (hESC-ECs) and human ESC-derived natural killer cells (hESC-NKs) for specific homing to breast cancer , and
(2) Identify tumor angiogenic factors that are responsible as chemoattractants. In addition, the incorporation of molecular imaging technology will further help us further assess the fate of transplanted stem cells and the target tumors.

Over the past 2 years, we have made substantial progress in this project. First, we have developed novel molecular imaging probes to detect non-invasively teratoma formation (i.e., A teratoma is an encapsulated tumor with tissue or organ components resembling normal derivatives of all three primary tissue types) from human ESCs [Cao F et al, Cancer Research 2009;69(7):2709-13]. We employed the same approach to image and track breast tumor formation de novo. Secondly, working with our collaborators at Stanford, we have also confirmed that mesenchymal stem cells (MSCs) can selectively home toward sub-cutaneouly injected tumors [Wang H et al, Stem Cells 2009]. Next, we are continuing to validate the homing process of hESC-ECs (endothelial cells) and hESC-NKs (immune natural killer T-cells) to subcutaneously injected breast tumors. Finally in this project, we have gathered substantial transciptional (mRNA/protein analysis) and functional profiling data on hESC-ECs, showing that they are indeed very similar to human endothelial cells [Li Z et al, PLoS ONE 2009]. Thus, we have created a new hESC line that stably express double and triple-fusion reporter gene consisting of firefly luciferase, red fluorescent protein, and herpes simplex virus thymidine kinase [Yu J et al, PLoS ONE 2009], which is currently being used to track homing of hESC derivatives to breast tumors. Finally, we are continuing to perfect the differentiation of hESCs into hESC-NKs with the aims of imaging their accumulation in breast tumors (mouse models) and the delivery of a cytotoxic agent selectively to tumor sites (both primary and metastatic).

In the future, once we are satisfied with these results, we plan to co-inject hESC-ECs and hESC-NKs and will use both bioluminescence and positron emission tomography (PET) imaging to monitor homing and ablation of these cells to breast tumor.



Noninvasive de novo imaging of human embryonic stem cell-derived teratoma formation.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Cao F, Li Z, Lee A, Liu Z, Chen K, Wang H, Cai W, Chen X, Wu JC
Yr: 2009 Vol: 69 Nbr: 7 Abs: Pg:2709-13

nAChRs mediate human embryonic stem cell-derived endothelial cells: proliferation, apoptosis, and angiogenesis.
Periodical:Journal of Developmental Origins of Health and Disease
Index Medicus:
Authors: Yu J, Huang NF, Wilson KD, Velotta JB, Huang M, Li Z, Lee A, Robbins RC, Cooke JP, Wu JC
Yr: 2009 Vol: 4 Nbr: 9 Abs: Pg:e7040

Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction.
Periodical:PLOS One
Index Medicus: PLOS One
Authors: Li Z, Wilson KD, Smith B, Kraft DL, Jia F, Huang M, Xie X, Robbins RC, et al, and Wu JC
Yr: 2009 Vol: 4 Nbr: 12 Abs: Pg:e8443