Reference SummaryNakamura JL, Cancer Res 2011 Jan 1;71(1):106-15

Title

Dose-dependent effects of focal fractionated irradiation on secondary malignant neoplasms in Nf1 mutant mice.

Authors

Nakamura JL; Phong C; Pinarbasi E; Kogan SC; Vandenberg S; Horvai AE; Faddegon BA; Fiedler D; Shokat K; Houseman BT; Chao R; Pieper RO; Shannon K

Journal

Cancer Res

Volume

71

Issue

1

Year

2011

Pages

106-15

Abstract

Secondary malignant neoplasms (SMN) are increasingly common complications of cancer therapy that have proven difficult to model in mice. Clinical observations suggest that the development of SMN correlates with radiation dose; however, this relationship has not been investigated systematically. We developed a novel procedure for administering fractionated cranial irradiation (CI) and investigated the incidence and spectrum of cancer in control and heterozygous Nf1 mutant mice irradiated to a moderate (15 Gy) or high dose (30 Gy). Heterozygous Nf1 inactivation cooperated with CI to induce solid tumors and myeloid malignancies, with mice developing many of the most common SMNs found in human patients. CI-induced malignancies segregated according to radiation dose as Nf1(+/-) mice developed predominately hematologic abnormalities after 15 Gy, whereas solid tumors predominated at 30 Gy, suggesting that radiation dose thresholds exist for hematologic and nonhematologic cancers. Genetic and biochemical studies revealed discrete patterns of somatic Nf1 and Trp53 inactivation and we observed hyperactive Ras signaling in many radiation-induced solid tumors. This technique for administering focal fractionated irradiation will facilitate mechanistic and translational studies of SMNs.

Links

J:167772 – Mouse Genome Informatics
21199799 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

5.26

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Bone osteosarcoma
  • cesium-137
Bone

observed

(C57BL/6 x 129/Sv)F1 CNS - Brain - Choroid plexus papilloma
  • cesium-137
CNS - Brain - Choroid plexus

6.67

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Erythrocyte hyperplasia Spleen

observed

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Erythrocyte hyperplasia
  • cesium-137
Spleen

observed

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma
  • cesium-137
Leukocyte - Monocyte - Macrophage - Histiocyte

observed

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Leukocyte - Myelocyte (Granulocyte) dysplasia Leukocyte - Myelocyte (Granulocyte)

observed

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Leukocyte - Myelocyte (Granulocyte) dysplasia
  • cesium-137
Leukocyte - Myelocyte (Granulocyte)

observed

(C57BL/6 x 129/Sv)F1 Leukocyte - Myelocyte (Granulocyte) tumor - malignant Leukocyte - Myelocyte (Granulocyte)

0

(C57BL/6 x 129/Sv)F1 Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • cesium-137
Leukocyte - Myelocyte (Granulocyte)

15 - 17

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Leukocyte - Myelocyte (Granulocyte) tumor - malignant Leukocyte - Myelocyte (Granulocyte)

13

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Leukocyte - Myelocyte (Granulocyte) tumor - malignant
  • cesium-137
Leukocyte - Myelocyte (Granulocyte)

19 - 40

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Leukocyte leukemia - myelomonocytic Leukocyte

observed

(C57BL/6 x 129/Sv)F1 Leukocyte lymphoma
  • cesium-137
Leukocyte

6.67

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Leukocyte lymphoma
  • cesium-137
Leukocyte

observed

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ PNS - Nerve sheath tumor - malignant
  • cesium-137
PNS - Nerve sheath

observed

(C57BL/6 x 129/Sv)F1 Pituitary gland adenoma
  • cesium-137
Pituitary gland

11.76

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Pituitary gland adenoma
  • cesium-137
Pituitary gland

observed

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ Spleen hyperplasia Spleen

observed

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ (Unspecified organ) carcinoma (Unspecified organ)

5.26

(C57BL/6 x 129/Sv)F1 (Unspecified organ) carcinoma - papillary
  • cesium-137
(Unspecified organ)

5.88

(C57BL/6 x 129/Sv)F1 (Unspecified organ) carcinoma - poorly differentiated
  • cesium-137
(Unspecified organ)

6.67

(C57BL/6 x 129/Sv)F1 (Unspecified organ) squamous cell carcinoma
  • cesium-137
(Unspecified organ)

5.88 - 6.67

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ (Unspecified organ) squamous cell carcinoma
  • cesium-137
(Unspecified organ)

observed

(C57BL/6 x 129/Sv)F1 (Unspecified organ) tumor (Unspecified organ)

12.5

(C57BL/6 x 129/Sv)F1 (Unspecified organ) tumor
  • cesium-137
(Unspecified organ)

23.53 - 26.67

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ (Unspecified organ) tumor (Unspecified organ)

10.53

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ (Unspecified organ) tumor
  • cesium-137
(Unspecified organ)

19.23 - 42.86

(C57BL/6 x 129/Sv)F1 (Unspecified organ) tumor - malignant (Unspecified organ)

0

(C57BL/6 x 129/Sv)F1 (Unspecified organ) tumor - malignant
  • cesium-137
(Unspecified organ)

15 - 17

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ (Unspecified organ) tumor - malignant (Unspecified organ)

13

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ (Unspecified organ) tumor - malignant
  • cesium-137
(Unspecified organ)

19 - 40

(C57BL/6 x 129/Sv)F1 (Unspecified organ) tumor - solid (Unspecified organ)

0

(C57BL/6 x 129/Sv)F1 (Unspecified organ) tumor - solid
  • cesium-137
(Unspecified organ)

6 - 17

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ (Unspecified organ) tumor - solid (Unspecified organ)

8

(C57BL/6 x 129/Sv)F1-Nf1tm1Tyj/+ (Unspecified organ) tumor - solid
  • cesium-137
(Unspecified organ)

5 - 31