BME PhD Proposal Seminar: Ryan Burke

The Role of Tumor-Associated Macrophages in Collagen I Ordering and Metastasis in Breast and Colorectal Cancers

Supervised by Prof. Edward Brown

Abstract

The onset of metastasis represents an onerous milestone in the progression of breast cancer, as metastasis to distant organs is frequently the cause of mortality in breast cancer patients. One indicator of breast cancer patient prognosis observed in the clinic is the infiltration of tumor-associated macrophages (TAMs) the presence of these leukocytes in breast tumors is correlated with poor outcome due to increased metastatic burden.

Metastasis requires tumor cells to enter the blood or lymphatic circulation, or exit the tumor-host interface, and such movement has been witnessed by multiple laboratories along collagen type I fibers which emit strong second harmonic generation (SHG) signal. SHG is a nonlinear optical phenomenon characteristic of materials that are highly ordered on a molecular level. Tumor cells move along SHG-emitting fibers faster than when they are moving independently of them, and they follow those fibers through the tumor-host interface and towards blood vessels. Due to the known capacity of TAMs to induce local fibroblasts to remodel collagen, and the ability of macrophages to alter collagen ordering as quantified by SHG during breast gland development, it is here hypothesized that TAMs are the cells ultimately responsible for creating and maintaining the network of metastasis-promoting, SHG-producing fibers in the breast tumor. The process of establishing and maintaining these fibers is of therapeutic interest, as disruption of this ordering regulation capacity exhibited by TAMs may lead to decreased metastatic burden in cases of breast cancer.

The tumor draining lymph node (TDLN) is one of the earliest sites for establishment and subsequent propagation of metastases. Significant changes in SHG signatures between TDLNs in nonmetastatic and early metastatic cases have been seen in our laboratory, implicating collagen ordering in the TDLN as measured by SHG as another possible mechanism for influencing metastatic outcome. Hence we hypothesize that macrophages are the cells ultimately responsible for creating and maintaining the network of metastasis-promoting, SHG-producing fibers in the TDLN as well.

The correlation between TAM presence and poor prognosis, interestingly, is not evidenced in all tumor types for instance, colorectal tumor prognoses are improved by TAM infiltration. We believe that the ability of TAMs to maintain collagen ordering may be hindered in the colon, and that the natural immune function of this cell type then dominates. As fibroblasts from different tissues have been shown to retain a positional memory, acting in a manner specific to their tissue of origin even after transplant into new tissue, this clinical observation is possibly explained by fibroblasts in the colon not responding in the same manner to received TAM signals as fibroblasts in the breast. We therefore hypothesize that it is the tumor bed, not the tumor type, that dictates the role of TAMs in maintaining the network of metastasis-promoting, SHG-producing fibers in a given tumor.