Procollagen Lysyl Hydroxylase 2 Is Essential for Hypoxia-Induced Breast Cancer Metastasis

Abstract

Metastasis is the leading cause of death among patients who have breast cancer. Understanding the role of the extracellular matrix in the metastatic process may lead to the development of improved therapies to treat cancer patients. Intratumoral hypoxia, found in the majority of breast cancers, is associated with an increased risk of metastasis and mortality. We found that in hypoxic breast cancer cells, HIF-1 activates transcription of the PLOD1 and PLOD2 genes encoding procollagen lysyl hydroxylases that are required for the biogenesis of collagen, which is a major constituent of the extracellular matrix. High PLOD2 expression in breast cancer biopsies is associated with increased risk of mortality. We demonstrate that PLOD2 is critical for fibrillar collagen formation by breast cancer cells, increases tumor stiffness, and is required for metastasis to lymph nodes and lungs.

HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells

“…Specific HIF target genes have been identified that are induced by hypoxia in breast cancer cells and promote critical steps in the metastatic process, including stromal cell recruitment (8,9), cancer cell migration (10), invasion and intravasation (11)(12)(13)(14)(15), margination and extravasation (5), and premetastatic niche formation (12,16). Increased expression of HIF target genes in primary breast cancers is associated with increased patient mortality (17,18).…”

Carcinogenesis of renal cell carcinoma reflected in HLA ligands: A novel approach for synergistic peptide vaccination design

“…[36][37][38] Additionally, multiple growth factor receptor pathways, e.g., epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and growth factor receptor pathway, were also found to be overrepresented. With angiogenesis being among the enriched processes, the vascular endothelial growth factor receptor (VEGFR) pathway likewise indirectly plays a role in the HLA ligand-dependent functional description of RCC.…”

“…20,21,[30][31][32][33][34][35] Furthermore, a vast array of new TAAs with corresponding peptides from HLA class I and II were discovered (Table 3). These included LOX and PLOD2, with high potential in engaging metastasis, [36][37][38] GRB2, ITPR3, and BCAR1, all of which are part of the EGFR pathway 39 and other growth factor receptor pathways, plus ENPEP, NRP2, TGFBI, THBS1, and THBS2, which are essential for angiogenesis. 40 It is notable that 16 out of 24 peptides listed in Table 3 were only found in one tissue sample each.…”

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

“…RAB22A gene expression was significantly increased in breast cancers (n = 530) compared with normal breast tissue (n = 63; P < 0.001; Fig 3A). RAB22A expression showed highly significant correlations with the expression of four representative HIF target genes (29,35,36) analyzed, P4HA1, P4HA2, VEGFA, and GLUT1 (P ≤ 0.0007; Fig. 3B).…”

“…In breast cancer, overexpression of HIF-1α or HIF-2α is associated with metastasis, treatment failure, and patient mortality (21)(22)(23)(24)(25)(26). HIFs are required for lymph node and lung metastasis in both autochthonous (27) and orthotopic (28)(29)(30) mouse models of breast cancer and activate the transcription of genes encoding proteins that are required for multiple steps in the invasion and metastasis of breast cancer cells (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38).…”