Engaging the vascular component of the tumor response
Posted: Fri Sep 15, 2017 9:39 am
Summary
Recent research has shed new light on the critical role of tissue microvasculature in regulating the tumor response to radiation and drugs. In this issue of Cancer Cell, Moeller et al. (2005) demonstrate that HIF-1 activation during the course of fractionated radiotherapy initiates pleiotropic adaptive responses in both tumor cells and the microvascular network, radiosensitizing tumor cells but concomitantly conferring tumor radioresistance due to protection of the microvascular endothelium. HIF-1 thus serves as a legitimate target for differential modulation of tissue response to radiation.
Next to last paragraph-
The studies by Garcia-Barros et al. (2003) showed that the early-phase microvascular endothelial apoptosis is mandatory for tumor cure, as MCA129 fibrosarcoma and B16 melanoma grown in apoptosis-resistant asmase−/− or Bax−/− mice were completely resistant to 15–20 Gy single-dose irradiation. These observations indicated that radiation-induced lesions in tumor cells were by themselves not lethal, and that their conversion to lethal damage is tightly coupled to the endothelial apoptotic response. The mechanism of the endothelial-tumor linkage is still unknown. It might involve leakage of a circulating factor, a bystander effect secondary to endothelial damage, or transient local ischemia/reperfusion produced by the acute microvascular dysfunction and its rapid reversal, perhaps by recruitment of circulating marrow-derived endothelial progenitor cells (Garcia-Barros et al., 2003). Of great interest are preliminary observations that human tumor specimens irradiated ex vivo within 15 min of surgical resection show the same rapid wave of endothelial apoptosis and dose-response profile for apoptosis as in the animal studies, except for grade IV glioblastoma, which exhibits apoptosis resistance (Fuks and Kolesnick, unpublished data). The endothelial responses in mouse and human tumor specimens both display an apparent threshold at 8–10 Gy and a maximal response at 20–25 Gy. The endothelial-stem cell linked mechanism would, therefore, not be activated by fractionated radiation schemes using <8 Gy/fraction, as employed by Moeller et al. This endothelial-stem cell linkage mechanism was also shown to mediate normal tissue damage after single-dose exposure of the intestines and lung (Kolesnick and Fuks, 2003; Paris et al., 2001), suggesting that this represents a generic response mechanism for mammalian tissue damage by large single-dose irradiation. The possibility that a similar crosstalk between microvasculature and tumor clonogens occurs during fractionated radiotherapy when the HIF-1-mediated endothelial protection is removed, such as reported by Moeller et al., represents a testable hypothesis.
Final paragraph-
In principle, the studies of Moeller et al. support the notion that fractionated radiotherapy, like single-dose radiation, engages a vascular component of the tumor response. In the case of fractionated radiotherapy, however, this response is largely attenuated by adaptive signals generated by HIF-1 activation. Hence, Moeller et al. suggest that HIF-1 may represent a valid target for radiosensitization via derepression of endothelial cell death. However, they caution that HIF-1 inactivation, if it is to be therapeutically efficacious, should be scheduled to optimize tumor cell radiosensitization. In contrast, the endothelial death signal produced by large-dose exposure (>8–10 Gy) may precede or be of sufficient magnitude to overcome HIF-1 anti-death protection. These provocative studies should open up new avenues for basic research into mechanisms of endothelial cell damage and the role of the microvascular response in therapy, potentially providing new pharmacologic targets for improving radiation and other anticancer treatments.
http://www.sciencedirect.com/science/ar ... 9aeaa92ffb
Hi all
The reason for this article post , in the brain section ,was to give light to a new concept of looking at Hypoxia
( HIF-1)* and how it's being understood to make or break the success of radiation in oncological treatments . Radioresistance as well as chemo resistance are what we know ASPS to be and if we can begin to overcome hypoxia predisposion , then in theory we may have more success stories to tell in using radiation . Especially with brain mets.
Hypoxia-Inducible Factor-1 (HIF-1)
http://molpharm.aspetjournals.org/content/70/5/1469
Recent research has shed new light on the critical role of tissue microvasculature in regulating the tumor response to radiation and drugs. In this issue of Cancer Cell, Moeller et al. (2005) demonstrate that HIF-1 activation during the course of fractionated radiotherapy initiates pleiotropic adaptive responses in both tumor cells and the microvascular network, radiosensitizing tumor cells but concomitantly conferring tumor radioresistance due to protection of the microvascular endothelium. HIF-1 thus serves as a legitimate target for differential modulation of tissue response to radiation.
Next to last paragraph-
The studies by Garcia-Barros et al. (2003) showed that the early-phase microvascular endothelial apoptosis is mandatory for tumor cure, as MCA129 fibrosarcoma and B16 melanoma grown in apoptosis-resistant asmase−/− or Bax−/− mice were completely resistant to 15–20 Gy single-dose irradiation. These observations indicated that radiation-induced lesions in tumor cells were by themselves not lethal, and that their conversion to lethal damage is tightly coupled to the endothelial apoptotic response. The mechanism of the endothelial-tumor linkage is still unknown. It might involve leakage of a circulating factor, a bystander effect secondary to endothelial damage, or transient local ischemia/reperfusion produced by the acute microvascular dysfunction and its rapid reversal, perhaps by recruitment of circulating marrow-derived endothelial progenitor cells (Garcia-Barros et al., 2003). Of great interest are preliminary observations that human tumor specimens irradiated ex vivo within 15 min of surgical resection show the same rapid wave of endothelial apoptosis and dose-response profile for apoptosis as in the animal studies, except for grade IV glioblastoma, which exhibits apoptosis resistance (Fuks and Kolesnick, unpublished data). The endothelial responses in mouse and human tumor specimens both display an apparent threshold at 8–10 Gy and a maximal response at 20–25 Gy. The endothelial-stem cell linked mechanism would, therefore, not be activated by fractionated radiation schemes using <8 Gy/fraction, as employed by Moeller et al. This endothelial-stem cell linkage mechanism was also shown to mediate normal tissue damage after single-dose exposure of the intestines and lung (Kolesnick and Fuks, 2003; Paris et al., 2001), suggesting that this represents a generic response mechanism for mammalian tissue damage by large single-dose irradiation. The possibility that a similar crosstalk between microvasculature and tumor clonogens occurs during fractionated radiotherapy when the HIF-1-mediated endothelial protection is removed, such as reported by Moeller et al., represents a testable hypothesis.
Final paragraph-
In principle, the studies of Moeller et al. support the notion that fractionated radiotherapy, like single-dose radiation, engages a vascular component of the tumor response. In the case of fractionated radiotherapy, however, this response is largely attenuated by adaptive signals generated by HIF-1 activation. Hence, Moeller et al. suggest that HIF-1 may represent a valid target for radiosensitization via derepression of endothelial cell death. However, they caution that HIF-1 inactivation, if it is to be therapeutically efficacious, should be scheduled to optimize tumor cell radiosensitization. In contrast, the endothelial death signal produced by large-dose exposure (>8–10 Gy) may precede or be of sufficient magnitude to overcome HIF-1 anti-death protection. These provocative studies should open up new avenues for basic research into mechanisms of endothelial cell damage and the role of the microvascular response in therapy, potentially providing new pharmacologic targets for improving radiation and other anticancer treatments.
http://www.sciencedirect.com/science/ar ... 9aeaa92ffb
Hi all
The reason for this article post , in the brain section ,was to give light to a new concept of looking at Hypoxia
( HIF-1)* and how it's being understood to make or break the success of radiation in oncological treatments . Radioresistance as well as chemo resistance are what we know ASPS to be and if we can begin to overcome hypoxia predisposion , then in theory we may have more success stories to tell in using radiation . Especially with brain mets.
Hypoxia-Inducible Factor-1 (HIF-1)
http://molpharm.aspetjournals.org/content/70/5/1469