Therapeutic Targeting of Vasculature in the Premetastatic and Metastatic Niches Reduces Lung Metastasis

Abstract

In the metastasis-targeted organs, angiogenesis is essential for the progression of dormant micrometastases to rapidly growing and clinically overt lesions. However, we observed changes suggesting angiogenic switching in the mouse lungs prior to arrival of tumor cells (i.e., in the premetastatic niche) in the models of breast carcinoma. This angiogenic switching appears to be caused by myeloid-derived suppressor cells recruited to the premetastatic lungs through complement C5a receptor 1 signaling. These myeloid cells are known to secrete several proangiogenic factors in tumors, including IL-1β and matrix metalloproteinase-9, and we found upregulation of these genes in the premetastatic lungs. Blockade of C5a receptor 1 synergized with antiangiogenic Listeria monocytogenes–based vaccines to decrease the lung metastatic burden by reducing vascular density and improving antitumor immunity in the lungs. This was mediated even when growth of primary breast tumors was not affected by these treatments. This work provides initial evidence that angiogenesis contributes to the premetastatic niche in rapidly progressing cancers and that inhibiting this process through immunotherapy is beneficial for reducing or even preventing metastasis.

Nanoparticle-Induced Complement Activation: Implications for Cancer Nanomedicine

“…In addition, AM reduced the number and maturation of lung dendritic cells by regulating TGF-β1 in the lung environment ( 121 ). Similar to findings from primary tumor sites ( 103 , 117 , 118 ), complement activation in the premetastatic niches seems to be associated with C1q-deposition and the classically pathway ( 122 ). C1q was demonstrated to bind to IgM-deposited in the premetastatic niche.…”

“…C1q was demonstrated to bind to IgM-deposited in the premetastatic niche. These IgM likely belong to natural IgM that bind dying or damaged cells as demonstrated by colocalization of Annexin V (binding to apoptotic cells) with IgM fluorescence in the lungs prior metastasis ( 122 ).…”

The Role of Complement in Angiogenesis

“…Blockade of C5aR1 with PMX53 or genetic C5aR1 deficiency resulted in reduced vascular density in the lung premetastatic niche and was associated with overall downregulation of proangiogenic pathways, therefore implicating C5a/C5aR1 in regulation of premetastatic angiogenesis. As anticipated, reduced angiogenesis in C5aR1 deficiency or blockade correlated with reduced infiltration of the lungs by MDSC [43]. Overall, this study provides (1) preliminary evidence for angiogenesis in the premetastatic niches, which may explain a lack of dormancy in some aggressive malignancies that manifest with rapid development of metastasis even when the primary tumor site cannot be identified [47], and (2) implicates complement in premetastatic angiogenesis through the regulation of MDSC (Figure 2).…”

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

“…Many anti-fibrotic therapies have met limited success in clinical trials for their ability to inhibit metastatic colonization and promote dormancy maintenance. However, the VEGF, PDGF and FGF inhibitor Nintedanib, which is used in the treatment of idiopathic pulmonary fibrosis, has been approved in some jurisdictions as a second line therapy in combination with conventional chemotherapy (e.g., pemetrexed) in NSCLC and renal cell carcinoma (201). By blocking the activation of fibroblasts to myofibroblasts, it significantly reduces the degree of ECM remodeling within tumors.…”