Previous studies have shown differences in expression levels of apoptosis regulatory proteins in non-Hodgkin lymphomas (NHLs) and indicated the correlation of procaspase-3 (proC-3) and caspase-3 activation to the response of chemotherapy. We investigated whether proC-3 expression in tumor biopsies of childhood NHLs is related to clinical outcome. Formalin-fixed paraffin-embedded tissues from 58 children with NHL were evaluated for proC-3 expression by immunochemistry analysis. The study included 20 cases of Burkitt lymphoma, 7 cases of diffuse large B-cell lymphoma, 18 cases of anaplastic large cell lymphoma (ALCL), and 13 cases of precursor lymphoblastic lymphoma. The highest expression level of proC-3 was observed in ALCL. In the multivariate analysis the higher clinical stage of disease and higher expression level of proC-3 were independent and appear to be significant prognostic factors of treatment failure. Our results suggest that the high expression level of proC-3 may be a powerful independent predictor of response to chemotherapy and progression-free survival in childhood NHLs.
ReiterA. Diagnosis and treatment of childhood non-Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program2007:285–296.
2.
Le DeleyMCReiterAWilliamsD. Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. Blood2008;111:1560–1566.
3.
BurkhardtBZimmermannMOschliesI. The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol2005;131:39–49.
4.
OudejansJJHarijadiACillessenSA. Absence of caspase-3 activation in neoplastic cells of nasopharyngeal carcinoma biopsies predicts rapid fatal outcome. Mod Pathol2005;18:877–885.
5.
SchimmerADPedersenIMKitadaS. Functional blocks in caspase activation pathways are common in leukemia and predict patient response to induction chemotherapy. Cancer Res2003;63: 1242–1248.
6.
AnwarSAmbrosRJenningsTA. Expression of cysteine protease protein 32 in prostatic adenocarcinoma correlates with tumor grade. Arch Pathol Lab Med2004;128:649–652.
7.
KrajewskaMWangHGKrajewskiS. Immunohistochemical analysis of in vivo patterns expression of CPP32/caspase-3/, a cell death protease. Cancer Res1997;57:1605–1613.
8.
KrajewskiSGascoyneRDZapataJM. Immunolocalization of the ICE/Ced-3-family protease, CPP32 (Caspase-3), in non-Hodgkin's lymphomas, chronic lymphocytic leukemia, and reactive lymph nodes. Blood1997;89:3817–3825.
9.
XerriLDevilardEAyelloC. Cysteine protease CPP32, but not Ich1-L, is expressed in germinal center B cells and their neoplastic counterparts. Hum Pathol1997;28:912–921.
10.
DurkopHHirschBHahnCSteinH. cIAP2 is highly expressed in Hodgkin-Reed-Sternberg cells and inhibits apoptosis by interfering with constitutively active caspase-3. J Mol Med2006;84:1432–1440.
11.
ten BergeRLMeijerCJLMDukersDF. Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma. Blood2002;99:4540–4546.
12.
DrakosERassidakisGZLaiR. Caspase-3 activation in systemic anaplastic large-cell lymphoma. Mod Pahol2004;17:109–116.
13.
MurisJJFCillessenSAGMVosW. Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas. Blood2005;105:2916–2923.
14.
LiHLSunBZFengQShangZC. Expression of surviving and caspase-3 in non-Hodgkin's lymphoma and their clinical significance. Ai Zheng2004;23:40–43.
15.
SwerdlowSHCampoEHarrisNL. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed.Lyon: IARC, 2008.
16.
MurphySB. Classification, staging and end results of treatment of childhood non-Hodgkin lymphomas: dissimilarities from lymphomas in adults. Semin Oncol1980;7:332–339.
17.
KaplanEIMeierP. Non-parametric estimation from incomplete observation. J Am Stat Assoc1958;53:457–481.
18.
HengartnerMO. The biochemistry of apoptosis. Nature2000;407: 770–776.
ManciniMNicholsonDWRoyS. The capase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling. J Cell Biol1998;140:1485–1495.
21.
StennickeHRJurgeusmeierJMShinH. Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem1998;273:27084–27090.
22.
AraiMSasakiASaitoNNakazatoY. Immunohistochemical analysis of cleaved caspase-3 detects high level of apoptosis frequently in diffuse large B-cell lymphomas of the central nervous system. Pathol Int2005;55:122–129.
23.
DukersDFOudejansJJVosWten BergeRLMeijerCJLM. Apoptosis in B-cell lymphomas and reactive lymphoid tissue always involves activation of caspase-3 as determined by a new in situ detection method. J Pathol2002;196:307–315.
24.
ElsawyWHAbdel KaderMElfarAGharibAEltrhonySDorghamY. Prognostic implications of caspase-3 expression in patients with diffuse large B-cell lymphoma (DLBCL) [ASCO abstract, post-meeting edition]. J Clin Oncol2006;24(Suppl):17500.
25.
MouraliJBenardALourencoFC. Anaplastic lymphoma kinase is a dependence receptor whose proapoptotic functions are activated by caspase cleavage. Mol Cell Biol2006;26:6209–6222.
26.
OyarzoMPDrakosEAtwellCAminHMMedeirosLJRassidakisGZ. Intrinsic apoptotic pathway in anaplastic large cell lymphoma. Hum Pathol2006;37:874–882.
27.
AtkinsonEABarryMDarmonAJ. Cytotoxic T lymphocyte-assisted suicide: caspase-3 activation is primarily the result of the direct action of granzyme B. J Biol Chem1998;273:21261–21266.
