Parathyroid Hormone-Related Protein-Induced Hypercalcemia in SCID Mice Engrafted With Adult T-Cell Leukemia Cells

Abstract

Parathyroid hormone-related protein (PTHrP) is considered to be one of the main causes of hypercalcemia associated with adult T-cell leukemia (ATL). To clarify the role of PTHrP and bone remodeling in the development of hypercalcemia in ATL, we examined the SCID mouse model of ATL that has previously been shown to mimic the disease in humans. Using this model, we found clear elevations in serum levels of calcium and C-terminal PTHrP (C-PTHrP). PTHrP mRNA was highly expressed in ATL cells proliferating in vivo. After the development of hypercalcemia, ATL mice were killed and bone histomorphometric analysis was performed. Bone volume was clearly decreased in the ATL mice. In comparison to control SCID mice, bone formation indices were very low in the ATL mice. Surprisingly, no significant difference was detected between the ATL mice and the control SCID mice in eroded surface/bone surface (ES/BS), a parameter of bone resorption. To our knowledge, the model presented here is the first animal model of ATL with humoral hypercalcemia. This is in contrast to previously reported, well-characterized animal models of human solid tumors associated with humoral hypercalcemia of malignancy (HHM). Furthermore, this model not only provides us with the opportunity to study the mechanisms underlying development of elevated calcium levels in ATL, but also allows us to test new therapeutic agents designed to treat hypercalcemia.

Macrophage Inflammatory Protein-1α Induces Hypercalcemia in Adult T-Cell Leukemia

“…These results indicate that MIP‐1α plays an important role in hypercalcemia in patients with ATL. However, because PTHrP has emerged as an important factor in the pathogenesis of hypercalcemia in ATL patients, (4,10) our findings in this study are contradictory to those previous observations. Previous studies reported that PTHrP cannot directly induce differentiation of hematopoietic precursor cells to osteoclasts and that high levels of PTHrP in the serum are not always associated with hypercalcemia in patients with ATL (11,12) .…”

“…Among these factors, PTHrP is considered to play an important role in stimulating osteoclasts, resulting in increased bone resorption. Immunodeficient mice implanted with leukemic cells from patients with ATL exhibited hypercalcemia and overexpressed PTHrP (10) . However, PTHrP cannot directly induce the differentiation of hematopoietic precursor cells to osteoclasts (11) .…”

Animal Models of Cancer-Associated Hypercalcemia

“…Additional techniques used to study the pathogenesis of HHM include the infusion of bioactive molecules (e.g., synthetic PTHrP) and the induction of squamous cell carcinoma by cutaneous application of dimethylbenzanthracene [50,118]. [127][128][129] Squamous cell carcinoma [128,130] Renal cell carcinoma [131,132] Urothelial cancer [133] Esophageal carcinoma [134,135] Melanoma [136,137] Mammary cancer [138] Pancreatic cancer [139] Colon cancer [140,141] Ovarian cancer [142] Adult T-cell leukemia/lymphoma SCID, NOD/scid [143][144][145] Multiple myeloma [146,147] Ovarian cancer [148] Allogenic models: The allogenic HSDM1 fibrosarcoma was derived from a mouse and results in progressive hypercalcemia 2-3 weeks following serial transfer into Swiss albino mice [119]. Evidence suggests that prostaglandin E 2 (PGE 2 ) is responsible for mediating the hypercalcemia, which is a unique, but uncommon mechanism of HHM.…”

Animal Models of Cancer-Associated Hypercalcemia

“…Adult T-cell leukemia/lymphoma (ATL): RVATL, MET-1, primary ATL cells: Immunodeficient SCID mice injected intraperitoneally with primary human ATL cells develop hypercalcemia and increased serum PTHrP concentrations [ 145 ]. The RV-ATL cells were derived from an ATL patient [ 163 ] and, when injected intraperitoneally into SCID/beige or NOD/scid mice, developed multicentric lymphoma, ascites and HHM.…”