HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism

Abstract

Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy (RT). While hypoxia increases tumor cell survival after RT because there is less oxygen to oxidize damaged DNA, whether signaling pathways triggered by hypoxia contribute to radiation resistance is poorly understood. For example, intratumoral hypoxia can increase hypoxia inducible factor 1 alpha (HIF-1α), which may regulate pathways that contribute to radiation sensitization or radiation resistance. To clarify the role of HIF-1α in regulating tumor response to radiation therapy, we generated a novel genetically engineered mouse model of soft tissue sarcoma with an intact or deleted HIF-1α. Deletion of HIF-1α sensitized primary sarcomas to RT in vivo. Moreover, cell lines derived from primary sarcomas lacking HIF-1α, or in which HIF-1α was knocked down, had decreased clonogenic survival in vitro, demonstrating that HIF-1α can promote radiation resistance in a cell autonomous manner. In HIF-1α intact and deleted sarcoma cells, radiation-induced reactive oxygen species (ROS), DNA damage repair, and activation of autophagy were similar. However, sarcoma cells lacking HIF-1α had impaired mitochondrial biogenesis and metabolic response after radiation which might contribute to radiation resistance. These results show that HIF-1α promotes radiation resistance in a cell autonomous manner.

Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo

“…In view of this decline in blood perfusion, it is not surprising that intratumour hypoxia is markedly increased under these conditions ( Figure 5). The aberrant increase in HIF-1a and its target genes, VEGF and CA9, in FSaII tumours observed in response to 15 Gy irradiation ( Figure 6) is in agreement with previous reports that high-dose irradiation induces significant upregulation of HIF-1a in various tumours [31,[35][36][37][38][39][40]43]. In the context of radiation-induced upregulation of HIF-1a, studies to date have shown that hypoxic cells in tumours are reoxygenated after irradiation and HIF-1a is activated in response to the reactive oxygens formed [36].…”

“…This type of high-dose hypofractionated irradiation has been shown to induce vascular damage in tumours [28][29][30], in turn, triggering secondary or indirect tumour cell death [28,[31][32][33][34]. Importantly, recent studies have reported that high-dose irradiation can also induce activation of various cell survival signals such as HIF-1a and its target genes in tumour cells [35][36][37][38][39][40].…”

“…HIF-1a is the master transcription factor upregulated under conditions of hypoxia that plays a crucial role in the survival and proliferation of tumour and stromal cells through transcription of numerous genes [35][36][37][38][39][40][41][42][43][44]. HIF-1a promotes angiogenesis and vasculogenesis by upregulating vascular endothelial growth factor (VEGF) [35,40] and C-X-C motif chemokine 12 (CXCL12) [44], and its activation is believed to play a pivotal role in relapse and metastasis of tumours after various treatments, including radiotherapy.…”

Hypoxia-inducible factor 1α predicts recurrence in high-grade soft tissue sarcoma of extremities and trunk wall

“…The therapeutic role of HIF-1 is particularly interesting in relation to radiotherapy, which is frequently used in the adjuvant setting 37. HIF-1 has been suggested as a potential candidate for targeted inhibition to improve radiation outcome 38.…”

De novo acetate production is coupled to central carbon metabolism in mammals

“…Mouse primary sarcoma cell lines were generated from Pax7 CreER-T2 , p53 FL/FL , LSLNras G12D tumors as described previously 48 . Briefly, tumor tissue was excised and digested with 5 mg/mL Collagenase Type I at 37 °C for 45 mins.…”