Engaging the vascular component of the tumor response

Treatment of brain metastases.
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D.ap
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Engaging the vascular component of the tumor response

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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as in the animal studies, except for grade IV glioblastoma, which exhibits apoptosis resistance (Fuks and Kolesnick, unpublished data).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. :P

Hypoxia-Inducible Factor-1 (HIF-1)
http://molpharm.aspetjournals.org/content/70/5/1469
Debbie
D.ap
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Blood vessels and the immune system talk to each other

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FULL STORY
Some cancer therapies aim at stopping tumor growth by affecting the blood vessels that nurture the tumor mass, while others act on the immune system attempting to eliminate the tumor. Researchers at Baylor College of Medicine have discovered that tumor blood vessels and the immune system influence each other's functions, and propose that considering these bilateral effects in cancer therapy might improve outcomes. The study appears in Nature.

https://www.sciencedaily.com/releases/2 ... 123533.htm
Debbie
D.ap
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Joined: Fri Jan 18, 2013 11:19 am

Specialized blood vessels enhance tumor-fighting immunotherapy

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“Sustained angiogenesis, the growth of new blood vessels, and the suppression of the immune system are hallmarks of cancer, with an increasing amount of evidence demonstrating that these two activities are interrelated. Therapies that prevent tumor blood vessel growth are often used in clinics to fight cancer -- but they are only effective in a particular subset of patients. Similarly, the recent successes to directly stimulate the immune system with inhibitors of negative immune checkpoint regulators -- such as antibodies against programmed cell death protein 1 (PD-1) or its ligand PD-1 -- has led to many clinical trials. However, only a minority of treated patients have responded to these immunotherapies, emphasizing the need to identify strategies that will increase response rates in patients. Dr. Elizabeth Allen and colleagues from the group of Prof. Dr. Gabriele Bergers at the VIB-KU Leuven Center for Cancer Biology provide evidence that anti-PD-L1 therapy can sensitize and prolong efficacy of anti-angiogenic therapy, and conversely, anti-angiogenic therapy can improve anti-PD-L1 treatment specifically when intratumoral HEVs are generated that facilitate enhanced whire cell infiltration, activity and tumor cell destruction.“

https://www.sciencedaily.com/releases/2 ... 084820.htm
Debbie
D.ap
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Posts: 4096
Joined: Fri Jan 18, 2013 11:19 am

Specialized blood vessels enhance tumor-fighting immunotherapy

Post by D.ap »

"A counterintuitive outcome

Interestingly, the team showed that combining anti-angiogenic and immune-stimulating therapies in the treatment of tumors in mouse models resulted in better therapeutic outcomes by providing white blood cell gates through which they can infiltrate cancers.

Dr. Elizabeth Allen (VIB-KU Leuven): "It was interesting to observe that this combination of immune system-activating and anti-angiogenic antibodies causes a positive feedback loop. The result is the growth of specific blood vessels that deliver cancer-fighting immune cells into the tumor. These high endothelial venules (HEVs) are normally found in lymphoid organs such as lymph nodes, where they help transport white blood cells. For the first time, we showed that the growth of HEVs can be therapeutically induced in tumors."

Describing the process

The results of the study indicate that the two therapies stimulated significant growth of HEVs in pancreatic and mammary tumors, leading to malignant cell death and tumor shrinkage. The next step in this research involves investigating how intratumoral HEVs are formed and maintained.

Prof. Gabriele Bergers (VIB-KU Leuven): "Understanding the underlying mechanisms of the process will contribute to the overarching goal of developing new therapeutic approaches to boosting the immune system in tumors."
Debbie
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