Hypoxia-inducible factors in mantle cell lymphoma: implication for an activated mTORC1→HIF-1α pathway

Abstract

Aberrant activation of phosphoinositide-3 kinase/Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) signaling is implicated in the pathogenesis of mantle cell lymphoma (MCL). We previously showed oncogenic activation of PI3K/Akt pathway in a subset of MCL patients. In this study, we investigated downstream the immunohistochemical expression of (Ser2448)pmTOR [indicative of mTOR complex 1 (mTORC1) activation status] as well as of hypoxia-inducible factor 1 alpha (HIF-1α), hypoxia-inducible factor 2 alpha (HIF-2α), p53, and p21 in the same series of MCL patients. Additionally, correlation of these proteins with activated Akt ((Ser473)pAkt) and established histological prognostic factors was examined. Thirty-five tissue samples (28 classical type and seven blastoid variant) were included. The neoplastic cells expressed (Ser2448)pmTOR in 61.7%, HIF-1α in 73.5%, HIF-2α in 23.5%, and p53 in 18.2% of patients, while p21 was negative in all examined samples. In addition, 72% of patients who expressed HIF-1α had also (Ser2448)pmTOR expression (p = 0.041). HIF-1α expression was also correlated to an elevated (≥30%) Ki-67 (p = 0.031) and blastoid variant of disease (p = 0.017). In conclusion, we report for the first time common expression of HIF-alphas, especially HIF-1α, in MCL patients. Furthermore, an overall activation of mTORC1→HIF-1α axis and a potential role of (Ser2448)pmTOR in the regulation of HIF-1α in MCL patients are suggested. Finally, HIF-1α appears to be associated with more aggressive disease. A pathogenetic role for both mTORC1 and HIF-1α in MCL is implied, which will possibly lead to more efficient target therapies.

Hypoxia Promotes Dissemination and Colonization in New Bone Marrow Niches in Waldenström Macroglobulinemia

“…Lymphomas were found to show hypoxic features, based on the expression of main endogenous hypoxic marker, HIF1a. Constitutive stabilization of HIF1a was found in the majority of patients with diffuse large B-cell lymphoma and follicular lymphoma (22), as well as in mantle cell lymphoma (18). Targeting hypoxia in solid tumors is one of the current approaches to prevent cancer angiogenesis, metastasis, and drug resistance, and it became also an emerging strategy in hematologic malignancies.…”

“…Tumor hypoxia activates adaptive transcriptional programs, including HIF1a, that promote cell survival, motility, invasiveness, drug resistance, and neoangiogenesis in multiple myeloma (16,17), associated with more aggressive tumor (18). We have shown that hypoxia induces egress of multiple myeloma cells from the bone marrow to the circulation and facilitates their homing to the new bone marrow niches in myeloma.…”

Resveratrol Suppresses Cancer Cell Glucose Uptake by Targeting Reactive Oxygen Species–Mediated Hypoxia-Inducible Factor-1α Activation

“…Kueck showed that decreased glucose uptake by resveratrol in several cancer cell lines was mediated by downregulated pyruvate kinase M2 expression through inhibition of mTOR signaling (16). HIF-1a induction in malignant cells is closely linked to PI3K/Akt and mTOR signaling (27)(28)(29), which are frequently involved in cancer cell proliferation, metabolism, and survival (30). In breast cancer cells, estrogen-induced HIF-1a accumulation was shown to occur through the PI3K/Akt pathway leading to mTOR phosphorylation (31).…”

Signaling Pathways in Lymphoma: Pathogenesis and Therapeutic Targets

“…PI3K/AKT/mTOR signaling plays a central role in the development of both solid and hematological cancers [50]. Several lines of evidence indicate that aberrant activation of this pathway is common in both Hodgkin's lymphoma (HL) and various NHL subtypes, including FL, MCL and DLBCL [51][52][53][54][55][56][57][58][59][60][61][62][63][64]. The malignant lymphoproliferative effect of increased PI3K activity was demonstrated in transgenic mice expressing an activated PI3K, resulting in an infiltrative lymphoproliferative disorder similar to that observed by loss of the tumor suppressor PTEN [65].…”