Impaired lymphatic function accelerates cancer growth

Abstract

Increased lymphangiogenesis is a common feature of cancer development and progression, yet the influence of impaired lymphangiogenesis on tumor growth is elusive. C3HBA breast cancer and KHT-1 sarcoma cell lines were implanted orthotopically in Chy mice, harboring a heterozygous inactivating mutation of vascular endothelial growth factor receptor-3, resulting in impaired dermal lymphangiogenesis. Accelerated tumor growth was observed in both cancer models in Chy mice, coinciding with reduced peritumoral lymphangiogenesis. An impaired lymphatic washout was observed from the peritumoral area in Chy mice with C3HBA tumors, and the number of macrophages was significantly reduced. While fewer macrophages were detected, the fraction of CD163+ M2 macrophages remained constant, causing a shift towards a higher M2/M1 ratio in Chy mice. No difference in adaptive immune cells was observed between wt and Chy mice. Interestingly, levels of pro- and anti-inflammatory macrophage-associated cytokines were reduced in C3HBA tumors, pointing to an impaired innate immune response. However, IL-6 was profoundly elevated in the C3HBA tumor interstitial fluid, and treatment with the anti-IL-6 receptor antibody tocilizumab inhibited breast cancer growth. Collectively, our data indicate that impaired lymphangiogenesis weakens anti-tumor immunity and favors tumor growth at an early stage of cancer development.

Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis

“…Tumor cells are commonly spread to tumor-draining lymph nodes in many types of cancer. There is ample evidence that lymphangiogenesis is actively induced by tumor cells and lymphangiogenic growth factors play an important role in lymphangiogenesis and distal organ metastasis [ 15 – 17 ]. For example, the proteolytic matured VEGF-C and VEGF-D interact with VEGFR-3 and upregulate lymphangiogenic activity [ 18 , 19 ]; the VEGF-A-VEGFR-2 axis also induces tumor lymphangiogenesis by inducing LEC proliferation [ 20 , 21 ].…”

The Lymphatic System: Integral Roles in Immunity

“…They also produce many other cytokines. For example, recent studies suggest that macrophage-sustaining cytokines like CSF-1 in tumors depend substantially upon the presence of lymphatic vessels (120). …”

Tumor-Derived Lactic Acid Contributes to the Paucity of Intratumoral ILC2s

“…Mirroring the decrease in the number of ILC2s, we found a reduced number of intratumoral T cells (CD3 + and CD8 + cells) and myeloid lineage cells (CD11b + cells) in B16F10 tumors compared with their less malignant counterparts, B16F0 tumors, with the exception of macrophages (F4/80 + cells), as their number remained unchanged ( Figures S3A and S3B). Since changes in vascular endothelium may influence the growth and contribute to the observed phenotype of B16F10 tumors, we assessed blood and lymphatic vessel densities (Lund et al, 2016;Steinskog et al, 2016). Although blood vessel density was reduced in B16F10 tumors compared with their less malignant counterparts, as analyzed by the number of CD31 + structures per field of view, the percentage of area covered by CD31 + structures was noticeably increased in B16F10 tumors (Figures S3C and S3D).…”