Metastasis remains the principal cause of cancer mortality. Furthermore, lymph node status is the most significant prognostic indicator for patient outcome in human solid cancer. The presence of cancer cells in the lymph node is associated with an absolute reduction in the 5-year rate of disease-free survival. Therefore, in cancers such as breast and melanoma, removal of the sentinel lymph node has become a standard approach to treat patients. However, in patients with lymph node involvement who also received adjuvant therapy, disease-free survival was improved. This suggests that tumor cells may take undetected residence in distal nodes and organs. Thus, the challenge is how to treat cancer cells that have spread to lymph nodes or distant organs in order to prevent their growth and ideally eradicate them from the body. A well-known class of adjuvant therapy is anti-angiogenesis inhibitors. Although angiogenesis is critical for growth and establishment of primary tumors, it is unknown how significant this process is for cancer cells that have metastasized. Through establishment of improved metastasis models, this project aims to investigate the angiogenic response in lymph node metastases. Clinical trials using anti-angiogenesis therapy have not fared as well as predicted. One reason for this outcome may be that this therapy was developed against the primary tumor growing in its native microenvironment. However, it is clear that the local microenvironment in which tumor cells grow greatly affects the growth rate, metabolism, vascularization and ultimately response to therapeutic intervention. Preliminary results in Aim 1 of this proposal suggest that the classical sprouting angiogenesis observed in the primary tumor site is not necessary for tumor growth in the lymph node, once cancer cells arrive. I hypothesize that the molecular and cellular mechanisms regulating tumor growth in early and late metastatic lymph nodes are independent of the formation of new blood vessels, contrary to what is seen in the primary tumor.
In Aim 1, I will use a combination of novel mouse models to test and reproduce these observations in vivo. Interestingly, within the metastatic tumor mass in the lymph nodes, the density of CD31 staining is significantly decreased with respect to the non-tumor area. While there is a normal distribution of blood capillaries in the metastatic lesions, there is a noticeable absence of high endothelial venules compared to the normal lymph node regions. Preliminary results in Aim 2 of the proposal suggest that remodeling of the lymph node vasculature leads to an inhibition of the immune response against cancer cells. I hypothesize that due to mechanical stress by tumor cells or a vascular dedifferentiation program induced by tumor cells, high endothelial venules lose the capacity to for lymphocyte trafficking and ultimately leads to loss of immune surveillance.
In Aim 2, I will investigate this mechanism and attempt to therapeutically intervene in order to enhance immune access to tumor cells. Collectively, these studies will contribute to understanding the progression of metastases in the lymph node, and may have implications for metastasis biology in general. Understanding mechanisms of cancer growth and survival in metastatic sites such as the lymph node is critical for the rational design and use of therapeutics, such as anti-angiogenesis adjuvants.
This project aims to establish novel models of lymph node metastasis in order to characterize a growing metastasis in its new microenvironment. The proposed project seeks to monitor early and late stages of metastatic growth in lymph nodes to investigate the biological triggers and opportunities for growth. Uncovering the biology of metastatic tumor growth in the lymph node will potentially lead to novel therapeutic design and targets for several types of cancer. Dr. Jones' access and exposure to the experience of his mentors and resources of his training environment will allow achievement of the planned experiments and effectively prepare him for an independent research career in the fields of vascular biology, cancer biology, and immunology.
| Jones, Dennis; Meijer, Eelco F J; Blatter, Cedric et al. (2018) Methicillin-resistant Staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction. Sci Transl Med 10: |
| Pereira, Ethel R; Kedrin, Dmitriy; Seano, Giorgio et al. (2018) Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice. Science 359:1403-1407 |
| Meijer, Eelco F J; Blatter, Cedric; Chen, Ivy X et al. (2017) Lymph node effective vascular permeability and chemotherapy uptake. Microcirculation 24: |
| Blatter, Cedric; Meijer, Eelco F J; Nam, Ahhyun S et al. (2016) In vivo label-free measurement of lymph flow velocity and volumetric flow rates using Doppler optical coherence tomography. Sci Rep 6:29035 |
| Jeong, Han-Sin; Jones, Dennis; Liao, Shan et al. (2015) Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases. J Natl Cancer Inst 107: |
