ALCAM/CD166 Is a TGF-β–Responsive Marker and Functional Regulator of Prostate Cancer Metastasis to Bone

Abstract

The dissemination of prostate cancer to bone is a common, incurable aspect of advanced disease. Prevention and treatment of this terminal phase of prostate cancer requires improved molecular understanding of the process as well as markers indicative of molecular progression. Through biochemical analyses and loss-of-function in vivo studies we demonstrate that the cell adhesion molecule ALCAM is actively shed from metastatic prostate cancer cells by the sheddase ADAM17 in response to TGFβ. Not only is this post-translational modification of ALCAM a marker of prostate cancer progression, the molecule is also required for effective metastasis to bone. Biochemical analysis of prostate cancer cell lines reveal that ALCAM expression and shedding is elevated in response to TGFβ signaling. Both in vitro and in vivo shedding is mediated by ADAM17. Longitudinal analysis of circulating ALCAM in tumor-bearing mice revealed that shedding of tumor, but not host-derived ALCAM is elevated during growth of the cancer. Gene-specific knockdown of ALCAM in bone-metastatic PC3 cells greatly diminished both skeletal dissemination and tumor growth in bone. The reduced growth of ALCAM knockdown cells corresponded to an increase in apoptosis (Caspase-3) and decreased proliferation (Ki-67). Together these data demonstrate that the ALCAM is both a functional regulator as well as marker of prostate cancer progression.

ALCAM is a Novel Cytoplasmic Membrane Protein in TNF-α Stimulated Invasive Cholangiocarcinoma Cells

“…Likewise, they demonstrated that ALCAM was highly expressed on the surface of prostate stem/ progenitor and cancer initiating cells (Jiao et al, 2012). In melanoma, pancreatic-and prostate cancers, up-regulation of ALCAM is associated with invasion and metastasis (Jannie et al, 2012;Fujiwara et al, 2014;Hansen et al, 2014). Our findings support these previous studies -ALCAM up-regulated both mRNA and protein levels when the CAA cell line was induced to invasive character.…”

BOK displays cell death‐independent tumor suppressor activity in non‐small‐cell lung carcinoma

“…However, sustained expression of MET and CD321 in TGFβ-treated BOK overexpressing cells shows epithelial state of the cells, thus confirming the BOK role in EMT inhibition. Moreover, overexpression of BOK downregulated membrane expression of CD166/ALCAM (Figure 6), which is implicated in NSCLC cancer cells migration and invasion in vitro (41) and its reduced expression inhibited skeletal metastasis in prostate cancer in vivo (42). …”

Shedding of epithin/PRSS14 is induced by TGF-β and mediated by tumor necrosis factor-α converting enzyme

“…In gastric cancer cells, TGF-b induces the shedding of membrane-anchored heparin-binding EGF-like growth factor and transactivates epidermal growth factor receptor (EGFR) [18]. In prostate cancer cells, TGF-b induces expression and shedding of the activated leukocyte cell adhesion molecule and enhances metastasis to bone [19]. In both case, the TGF-b-induced shedding is mediated through activation of TACE, also known as ADAM17.…”