Mechanisms of tumor microenvironment in promoting metastasis

Tumor tissues contain diverse cell populations that relentlessly cross-communicate with each other in the tumor microenvironment. In addition to malignant cells, infiltration of other host cells including inflammatory cells, fibroblasts, and cells in the vessel walls in tumors significantly contribute to tumor growth and metastasis. The diversity of cell populations in the tumor microenvironment determines the production of various growth factors and cytokines, which are often upregulated. Although these signaling molecules interact with their specific receptors to trigger signaling events in the targeted cells, they often crosstalk to each other to elicit additive or synergistic effects in the tumor tissue. This thesis work provides several examples of such complex interactions between various cellular and signaling components in the tumor microenvironment in promoting metastasis. We particularly focused our research on angiogenesis-related signaling events to identify molecular mechanisms underlying tumor metastasis.

In paper I, we show that expression levels of PDGF-BB in tumor cells can serve as a surrogate marker for drug response. One of the most surprising findings is that high levels of tumor cell-derived PDGF-BB ablates pericytes from the tumor microvasculature. Mechanistically, tumor cell-derived PDGF-BB attracts pericytes from the vessel wall toward tumor cells, leaving the endothelium unprotected. Ablation of pericytes leads to exposure of primitive microvessels susceptible for tumor cell intravasation. As a result, inhibition of the PDGF-BB-PDGFR signaling in high PDGF-BB-producing tumors prevents tumor cell intravasation and metastasis. Conversely, inhibition of the PDGF-BB-PDGFR signaling in PDGF-BB negative tumors ablates pericytes from the tumor microvasculature and promotes tumor metastasis. Therefore, PDGF-BB levels may serve as a potential surrogate marker for predicting anti-PDGF therapeutic outcomes.

In paper II, we uncover a novel mechanism of pericytes in promoting tumor metastasis. In PDGF-BB-activated pericytes, genome-wide profiling shows that IL-33 is the most upregulated gene among all genes. ST2 as a receptor for IL-33 is abundantly expressed in macrophages. In various in vitro and in vivo experimental settings, IL-33 promotes the polarization of macrophages to an M2 subtype. Gain- and loss-of-function experimental data show that IL-33-activated macrophages promote tumor metastasis. Together, this work reveals a previously unknown mechanism underlying pericyte-mediated tumor metastasis and targeting the PDGF-PDGFR-IL-33-ST2 signaling axis provides a novel therapeutic option for treatment of cancer patients.

Paper III identifies VEGF-B; a VEGFR-1 exclusive binding ligand, as a promoter of tumor metastasis through a VEGF-A-independent mechanism. VEGF-B remodels tumor vessels to become pseudonormalized and highly leaky by ablating pericytes from tumor vessels. The highly leaky tumor vessels permit tumor cell intravasation into the circulation and facilitate metastasis. Importantly, high expression levels of VEGF-B in cancer patients correlate with poor prognosis. In the last paper, we show that FGF-2 and VEGF-C collaboratively promote lymphangiogenesis. For the first time, we show that the VEGFR3 signaling is crucial for non-VEGF-C-induced lymphatic networks. Importantly, FGF-2 and VEGF-C synergistically promotes metastasis.

Altogether, this thesis work uncovered several novel mechanisms underlying tumor metastasis and targeting these signaling pathways may offer new opportunities for effective treatment of cancer patients.

List of scientific papers

I. Hosaka K, Yang Y, Seki T, Nakamura M, Andersson P, Rouhi P, Yang X, Jensen L, Lim S, Feng N, Xue Y, Li X, Larsson O, Ohhashi T, Cao Y. Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis. Nature Communications. 2013;4:2129.
https://doi.org/10.1038/ncomms3129

II. Yang Y, Andersson P, Hosaka K, Zhang Y, Cao R, Iwamoto H, Yang X, Nakamura M, Wang J, Zhuang R, Morikawa H, Xue Y, Braun H, Beyaert R, Samani N, Nakae S, Hams E, Dissing S, Fallon PG, Langer R, Cao Y. The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumor-associated macrophages. Nature Communications. 2016;7:11385.
https://doi.org/10.1038/ncomms11385

III. Yang X, Zhang Y, Hosaka K, Andersson P, Wang J, Tholander F, Cao Z, Morikawa H, Tegnér J, Yang Y, Iwamoto H, Lim S, Cao Y. VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for human cancer patients. Proc Natl Acad Sci U S A. 2015;112(22):E2900-9.
https://doi.org/10.1073/pnas.1503500112

IV. Cao R, Ji H, Feng N, Zhang Y, Yang X, Andersson P, Sun Y, Tritsaris K, Hansen AJ, Dissing S, Cao Y. Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proc Natl Acad Sci U S A. 2012;109(39):15894-9.
https://doi.org/10.1073/pnas.1208324109