Disseminated carcinomatosis of the bone marrow (DCBM) is a widespread metastasis with a hematologic disorder that is mainly caused by gastric cancer. Although it commonly occurs as a manifestation of recurrence long after curative treatment, the precise mechanism of relapse from dormant status remains unclear. Granulocyte colony-stimulating factor (G-CSF) can promote cancer progression and invasion in various cancers. However, the potential of G-CSF to trigger recurrence from a cured malignancy has not been reported.

A 55-year-old Japanese woman was diagnosed with Ewing sarcoma localized on the fifth lumbar vertebrae 6 years after curative gastrectomy for T1 gastric cancer. After palliative surgery to release nerve compression, pathological diagnosis of the resected specimen was followed by curative radiation and chemotherapy. During treatment, G-CSF was administered 32 times for severe neutropenia prophylaxis. Eight months after completing definitive treatment, she complained of severe back pain and was diagnosed as multiple bone metastases with DCBM from gastric cancer. Despite palliative chemotherapy, she died of disseminated intravascular coagulation 13 d after the diagnosis. Immunohistochemical examination of the autopsied bone marrow confirmed a diffuse positive staining for the G-CSF receptor (G-CSFR) in the relapsed gastric cancer cell cytoplasm, whereas the primary lesion cancer cells showed negative staining for G-CSFR. In this case, G-CSF administration may have been the key trigger for the disseminated relapse of a dormant gastric cancer.

When administering G-CSF to cancer survivors, recurrence of a preceding cancer should be monitored even after curative treatment.

• Disseminated bone marrow carcinomatosis
• Gastric cancer
• Granulocyte colony-stimulating factor
• Cancer survivor
• Immunostaining
• Case report

• HIF-1α
• HIF-2α
• ROS

• Bones
• Fracture healing
• Immune response
• Mesenchymal stem cells
• Trauma

Granulocyte colony-stimulating factor (G-CSF)-producing tumors are rare and are associated with a poor prognosis when they occur in the lungs and the head and neck region. Positron emission tomography/computed tomography has been reported to show systemic specific accumulation of fluorodeoxyglucose in these cases, but the systemic complications associated with the cytokines produced are not well known. We herein present the case of a G-CSF-producing maxillary sinus squamous cell carcinoma in a 73-year-old Japanese woman with a vertebral fracture and splenomegaly. These findings are known severe adverse events of high-dose recombinant human G-CSF treatment. The aim of the present study was to further discuss the hypothesis that cytokines produced by solid tumors may induce spinal vertebral fracture and splenomegaly.

• complication
• granulocyte colony-stimulating factor
• head and neck cancer
• splenomegaly
• vertebral fracture

• bone metastasis
• immuno-oncology
• immunotherapy
• osteoimmuno-oncology
• osteoimmunology

• Animals
• Bone Neoplasms/immunology
• Bone Neoplasms/secondary
• Humans
• Immunotherapy/methods
• Neoplasm Metastasis/immunology
• Neoplasm Metastasis/pathology
• Tumor Microenvironment/immunology

Granulocyte colony-stimulating factor (G-CSF) is an important immune factor that mediates bone metabolism by regulating the functions of osteoclasts and osteoblasts. Bone loss is a serious and progressive result of periodontitis. However, the mechanisms underlying the effects of G-CSF on periodontal inflammation have yet not been completely elucidated. Here, we examined whether an anti-G-CSF antibody could inhibit bone resorption in a model of experimental periodontitis and investigated the local expression of G-CSF in periodontal tissues.

Experimental periodontitis was induced in mice using ligatures. The levels of G-CSF in serum and bone marrow were measured; immunofluorescence was then performed to analyze the localization and expression of G-CSF in periodontal tissues. Mice with periodontitis were administered anti-G-CSF antibody by tail vein injection to assess the inhibition of bone resorption. Three-dimensional reconstruction was performed to measure bone destruction‐related parameters via micro-computed tomography analysis. Immunofluorescence staining was used to investigate the presence of osteocalcin-positive osteoblasts; tartrate-resistant acid phosphatase (TRAP) staining was used to observe osteoclast activity in alveolar bone.

The level of G-CSF in serum was significantly elevated in mice with periodontitis. Immunofluorescence analyses showed that G-CSF was mostly expressed in the cell membrane of gingival epithelial cells; this expression was enhanced in the periodontitis group. Additionally, systemic administration of anti-G-CSF antibody significantly inhibited alveolar bone resorption, as evidenced by improvements in bone volume/total volume, bone surface area/bone volume, trabecular thickness, trabecular spacing, and trabecular pattern factor values. Immunofluorescence analysis revealed an enhanced number of osteocalcin-positive osteoblasts, while TRAP staining revealed reduction of osteoclast activity.

G-CSF expression levels were significantly up-regulated in the serum and gingival epithelial cells. Together, anti-G-CSF antibody administration could alleviates alveolar bone resorption, suggesting that G-CSF may be one of the essential immune factors that mediate the bone loss in periodontitis.

• bone cancer
• pathogenesis

• R01 CA182435 NCI NIH HHS
• R01 CA239343 NCI NIH HHS
• R21 CA241234 NCI NIH HHS
• U01 CA185148 NCI NIH HHS
• rudolf becker foundation for translational prostate cancer research

• Antitumor immunity
• Immune suppression
• Immunotherapy
• Myeloid-derived suppressor cells
• Tumor progression

• Granulocyte colony-stimulating factor
• Immunology
• Neutrophils
• Osteoclasts
• Periodontitis

The granulocyte colony-stimulating factor (G-CSF) is the most commonly used hematopoietic growth factor recombinant DNA technology. It affects bone metabolism by modulating both osteoclast and osteoblast functions. The aim of the present study was to investigate the effects of short-term use of G-CSF on bone metabolism in children with leukemia and solid tumors.

Thirty-six patients with a malignancy who received G-CSF therapy according to chemotherapy protocols and another 20 growth factor-free cancer patients who were enrolled as controls were included in the study. The serum osteocalcin and urinary free deoxypyridinoline levels were measured before the start of G-CSF therapy, on day 3 after treatment, and 7 days after G-CSF therapy was discontinued. In the control group, the measurements were made during corticosteroid and methotrexate-free chemotherapy.

The mean osteocalcin level (8.6±2.3 ng/mL) from before the onset of treatment decreased significantly (7.7±2.3 ng/mL) on day 3 of G-CSF therapy and significantly increased after 7 days of G-CSF therapy (7.9±2.2 ng/mL) (p<0.001 and p<0.001, respectively), which was still significantly lower than the pre-G-CSF values (p<0.001). The urinary free deoxypyridinoline level significantly increased on day 3 of G-CSF treatment (25.6±6.5 nmol/mmol Cr) and significantly decreased after 7 days of G-CSF therapy (22.6±6.4 nmol/mmol Cr) (p<0.001 and p<0.001, respectively), which was still significantly higher than the values recorded before G-CSF therapy (p<0.001).

The findings show that the short-term use of G-CSF in children with cancer can affect bone metabolism and can play a role in metabolic changes. Decreased osteoblastic activity and increased osteoclastic activity suggest that osteoporosis may be associated with bone pain in these patients.

• Bone
• cancer
• granulocyte colony-stimulating factor
• hematopoietic growth factor

• B cells
• fusion cytokine
• hematopoietic stem cells

Hematopoietic stem cells (HSCs) in the endosteum of mesoderm-derived appendicular bones have been extensively studied. Neural crest-derived bones differ from appendicular bones in developmental origin, mode of bone formation and pathological bone resorption. Whether neural crest-derived bones harbor HSCs is elusive. Here, we discovered HSC-like cells in postnatal murine mandible, and benchmarked them with donor-matched, mesoderm-derived femur/tibia HSCs, including clonogenic assay and long-term culture. Mandibular CD34 negative, LSK cells proliferated similarly to appendicular HSCs, and differentiated into all hematopoietic lineages. Mandibular HSCs showed a consistent deficiency in lymphoid differentiation, including significantly fewer CD229 + fractions, PreProB, ProB, PreB and B220 + slgM cells. Remarkably, mandibular HSCs reconstituted irradiated hematopoietic bone marrow in vivo, just as appendicular HSCs. Genomic profiling of osteoblasts from mandibular and femur/tibia bone marrow revealed deficiencies in several HSC niche regulators among mandibular osteoblasts including Cxcl12. Neural crest derived bone harbors HSCs that function similarly to appendicular HSCs but are deficient in the lymphoid lineage. Thus, lymphoid deficiency of mandibular HSCs may be accounted by putative niche regulating genes. HSCs in craniofacial bones have functional implications in homeostasis, osteoclastogenesis, immune functions, tumor metastasis and infections such as osteonecrosis of the jaw.

• Adaptive immune system
• Bone biology
• Ectopic bone
• Heterotopic ossification
• Trauma