The Serum Glycoprotein Fetuin-A Promotes Lewis Lung Carcinoma Tumorigenesis via Adhesive-Dependent and Adhesive-Independent Mechanisms

Abstract

Fetuin-A is a serum glycoprotein in the cystatin family associated with the regulation of soft tissue calcification. We tested the role of systemic fetuin in tumor cell growth and metastasis by injecting Lewis lung carcinoma (LLC) cells into fetuin-A null and their wild-type (WT) littermate control C57BL/6 mice via the tail vein, s.c., and intrasplenic routes. In the experimental metastasis assay, the lungs of the WT mice were filled with metastatic nodules, whereas the lungs of the fetuin-A null mutant mice were virtually free of colonies at the end of 2 weeks. Lung colonization responded to the levels of serum fetuin-A in a dose-dependent manner, as observed by the formation of half as many colonies in mice heterozygous for the fetuin-A locus compared with homozygous WT mice and restoration of lung colonization by the administration of purified fetuin-A to fetuin-A-null mice. Serum fetuin-A also influenced the growth of LLC cells injected s.c.: fetuin-A-null mice developed small s.c. tumors only after a substantial delay. Similarly, intrasplenic injection of LLC cells resulted in rapid colonization of the liver with metastasis to the lungs within 2 weeks in the WT but not fetuin-A null mice. To examine the mechanism by which fetuin-A influences LLC colonization and growth, we showed that LLC tumor cells adhere to fetuin-A in a Ca2+-dependent fashion, resulting in growth of the tumor cells. These studies support the role of fetuin-A as a major growth promoter in serum that can influence tumor establishment and growth.

Comprehensive Proteome Analysis of Malignant Pleural Effusion for Lung Cancer Biomarker Discovery by Using Multidimensional Protein Identification Technology

“…AHSG is synthesized in the adult liver and many other organs during embryogenesis. The protein is selectively accumulated in the bone matrix and inhibits pathological mineralization due to its high affinity to calcium, barium and hydroxyapatite. − Recent studies have shown that AHSG regulates immune response, cell adhesion, promotes growth and inhibits tumor progression. − ANG, the fifth member of the pancreatic ribonuclease superfamily, is a tRNA-specific ribonuclease that abolishes protein synthesis by specifically hydrolyzing cellular tRNAs and triggers a number of biological processes, including cell migration, invasion, proliferation, angiogenesis and formation of tubular structures. − CST3, one of the extracellular type II cystatins, is a low molecular-weight protein that acts as a strong inhibitor of cysteine peptidases of the papain family . CST3 proteins are expressed in various tissues, where they regulate normal proteolysis and participate in disease pathology. , Numerous studies suggest that CST3 participates in multiple steps of cancer progression, such as transformation of cells to a malignant state, tumor growth, invasion and metastasis .…”

Designed Synthesis of Dual Emitting Silicon Quantum Dot for Cell Imaging: Direct Labeling of Alpha 2-HS-Glycoprotein

“…48 The concentration of AHSG in human serum is ∼1.5 mg/mL during fetal development and ∼0.5 mg/mL in adult blood. 49 AHSG is mainly synthesized and secreted by the liver (>95%) and the rest by adipocyte, kidney, placenta, tongue, etc. Elevated circulating Fetuin A is associated with several illnesses such as type 2 diabetes mellitus, obesity, non alcoholic fatty liver disease (NAFLD), dyslipidemia, artherosclerosis, cardiovascular disease, etc.…”

“…Cancer cells have surface receptor Annexin 2 and Annexin 6, which serve as receptors for AHSG. 49 As a result, the glycoprotein can enter the breast carcinoma cells and helps their growth. 52 Thus, AHSG directed cell imaging may help in detecting the role of the particular protein inside the cell.…”

“…Alpha 2 Heremens Schimdt Glycoprotein (AHSG) (also known as Alpha2-HS-glycoprotein or Fetuin A) is a serum glycoprotein of the cystatin super family and negative acute phase protein . The concentration of AHSG in human serum is ∼1.5 mg/mL during fetal development and ∼0.5 mg/mL in adult blood . AHSG is mainly synthesized and secreted by the liver (>95%) and the rest by adipocyte, kidney, placenta, tongue, etc.…”

“…Another interesting feature of AHSG is that it preferentially stimulates the growth of tumor cells (not normal cells). Cancer cells have surface receptor Annexin 2 and Annexin 6, which serve as receptors for AHSG . As a result, the glycoprotein can enter the breast carcinoma cells and helps their growth .…”