Neovascularization After Irradiation
Neovascularization After Irradiation
Local relapse of tumors after radiation therapy remains a challenge in oncology. To devise rational approaches for preventing this relapse, we have to improve our understanding of how new vessels form in previously irradiated tumors. We propose that tumor regrowth after local irradiation is dependent on blood vessel formation by local endothelial cells without the need for recruitment of endothelial precursor cells from distant nonirradiated tissues or bone marrow. We also suggest that infiltrating myeloid bone marrow–derived cells promote survival of local endothelial cells during the early period after irradiation and angiogenesis during the later stage of tumor regrowth, both via paracrine mechanisms.
Radiation therapy is a widely used method of killing proliferating tumor cells to achieve locoregional control of cancer. Unfortunately, initial tumor response is often followed by relapse. For decades, most radiobiological studies have been focused on the radiosensitivity of cancer cells. However, it is becoming increasingly clear that multiple changes in tumor stroma—including but not limited to hypoxia—may also determine treatment outcome. Moreover, although radiotherapy is a localized treatment, tumor regrowth may be substantially affected by systemic factors.
In particular, ionizing radiation intensifies the recruitment of "distal" stroma, in the form of inflammatory bone marrow–derived cells (BMDCs), to the tumor and its surroundings. As shown recently, these BMDCs of myeloid lineage may facilitate tumor relapse post-radiation. After a large single dose of local irradiation in preclinical tumor models in mice, two waves of myeloid BMDCs arrive at the treatment site. The first occurs 3–5 days post-radiation and is followed by a delayed influx of myeloid BMDCs after about 2 weeks. The initial wave is likely mediated by increased expression of "stress-response" molecules in tumors in direct response to radiation (vascular endothelial growth factor, stromal cell–derived factor 1 alpha, endothelial adhesion molecules), and the second is associated with tissue damage leading to hypoxia and activation of hypoxia-responsive genes (hypoxia inducible factor 1 alpha, stromal cell–derived factor 1 alpha, and vascular endothelial growth factor). The tumor-protective effect of the recruited myeloid BMDCs has been attributed to their ability to support tumor vasculature after irradiation in a paracrine manner—analogous to that described for radiation-naive tumors. However, the contributions of specific provascular myeloid BMDC populations, including M2-type macrophages, Tie2 monocytes and Gr-1 monocytes, or neutrophils, and the signals that mediate their recruitment and local function are not well characterized.
Moreover, the status of tumor vasculature at certain post-radiation stages remains largely unclear. In general, the tolerance of tumor vessels to irradiation may play a dual role in radiotherapy. A stable vasculature is required to maintain the blood perfusion necessary for cancer cell (re)oxygenation, and therefore radiosensitization, throughout the course of treatment, which is usually fractionated in the clinic. However, functional vessels and viable endothelial cells (ECs) are undesirable after any type of tumor irradiation because they might support the survival and growth of remaining cancer cell clonogens and thus promote the relapse. Despite the intense research on tumor oxygenation during irradiation, little is known about the dynamics of vascular changes and the mechanisms of neovascularization after radiation.
This commentary focuses on revascularization of tumors after non-curative radiotherapy, which is arguably the least understood contributor to tumor regrowth post-radiation. In particular, we address the unanswered question regarding the source of neovessels in relapsing tumors. Many tumor-associated ECs are undoubtedly killed or at least deprived of proliferative capacity by high-dose irradiation. But are those ECs that survive still capable of reestablishing a tumor vasculature during post-radiation recurrence? Or do other players (eg, recruited BMDCs) become more important? To our knowledge, there is no consensus in the literature on this point.
Some researchers proposed that local tumor irradiation at a single dose of 15–20 Gy or higher can "sterilize" sufficient ECs inside and around the tumor to abrogate the growth and sprouting of irradiated vessels (angiogenesis), thereby forcing the tumor to rely on vasculogenesis by infiltrating cells. Indeed, because bone marrow–resident cells or circulating BMDCs receive very little exposure to radiation during tumor treatment, it is reasonable to expect that the recruitment and further incorporation of these cells in tumor vessels would be much more substantial post-radiation vs radiation-naive tumors. If supported by compelling data, this attractive hypothesis would also reconcile an unresolved yet controversial issue in the literature about whether gross tumor response to radiation is associated with vascular damage. Therefore, the influx of bone marrow–derived vascular precursors to tumors during the regrowth stage post-radiation, when additional cells are necessary for building new vessels, has recently been investigated. However, neither study could detect any substantial incorporation of BMDCs within the vessels of tumors regrowing post-radiation. Thus, BMDC-based vasculogenesis is not a major contributor to new vessel formation in irradiated tumors. An obvious alternative mechanism is post-radiation angiogenesis, provided local ECs survive and remain functional.
Is there any proof in the literature to support this mechanism? To address this question, we summarize below and in Table 1, the previous preclinical observations, and propose a model reconstructing the dynamics of events in tumor-associated ECs and vasculature in general after a single high dose (approximately 20 Gy) of local gamma- or x-ray irradiation. Such non-curative treatments have been widely used in animal studies and allow a better separation and understanding of post-radiation effects than fractionated irradiation regimens. This analysis is particularly timely because therapies using a single dose or a few large fractions of radiation are being increasingly tested in the clinic (eg, stereotactic body/ablative radiotherapy or radiosurgery). Although no specific data exist, it has been postulated that such irradiation induces more damage to tumor vasculature than conventional fractionated radiotherapy, which provides a crucial therapeutic benefit. The available data are fairly incomplete and inconsistent. Most studies have focused on early vascular effects, and the late post-radiation stages have been less explored. Moreover, the older studies lacked a specific marker for EC staining, and the more recent reports rarely evaluated ECs and vessel structure and function simultaneously. Clearly, there is no experimental consensus on the question of revascularization after radiation, and a logical conceptual framework would help direct future work in this area.
We propose such a framework, in which the tumor vascular response to irradiation occurs in four stages, which approximately corresponds to the phases of tumor size changes (Figure 1).
(Enlarge Image)
Figure 1.
Proposed model of tumor growth and corresponding changes in endothelial cell/vessel status after single-dose local irradiation (R). After irradiation (approximately 20 Gy), tumors normally continue to enlarge for a few days, then shrink (depicted) or become stable in size (not shown), and then they start to regrow. The time scale varies for different tumors, but the whole span is typically a few weeks. We have divided the post-radiation events into four different stages (I–IV), including two waves of the vessel-rescuing recruitment of myelomonocytes. Note that angiogenesis is required in stage IV only. EC = endothelial cell.
Abstract and Introduction
Abstract
Local relapse of tumors after radiation therapy remains a challenge in oncology. To devise rational approaches for preventing this relapse, we have to improve our understanding of how new vessels form in previously irradiated tumors. We propose that tumor regrowth after local irradiation is dependent on blood vessel formation by local endothelial cells without the need for recruitment of endothelial precursor cells from distant nonirradiated tissues or bone marrow. We also suggest that infiltrating myeloid bone marrow–derived cells promote survival of local endothelial cells during the early period after irradiation and angiogenesis during the later stage of tumor regrowth, both via paracrine mechanisms.
Introduction
Radiation therapy is a widely used method of killing proliferating tumor cells to achieve locoregional control of cancer. Unfortunately, initial tumor response is often followed by relapse. For decades, most radiobiological studies have been focused on the radiosensitivity of cancer cells. However, it is becoming increasingly clear that multiple changes in tumor stroma—including but not limited to hypoxia—may also determine treatment outcome. Moreover, although radiotherapy is a localized treatment, tumor regrowth may be substantially affected by systemic factors.
In particular, ionizing radiation intensifies the recruitment of "distal" stroma, in the form of inflammatory bone marrow–derived cells (BMDCs), to the tumor and its surroundings. As shown recently, these BMDCs of myeloid lineage may facilitate tumor relapse post-radiation. After a large single dose of local irradiation in preclinical tumor models in mice, two waves of myeloid BMDCs arrive at the treatment site. The first occurs 3–5 days post-radiation and is followed by a delayed influx of myeloid BMDCs after about 2 weeks. The initial wave is likely mediated by increased expression of "stress-response" molecules in tumors in direct response to radiation (vascular endothelial growth factor, stromal cell–derived factor 1 alpha, endothelial adhesion molecules), and the second is associated with tissue damage leading to hypoxia and activation of hypoxia-responsive genes (hypoxia inducible factor 1 alpha, stromal cell–derived factor 1 alpha, and vascular endothelial growth factor). The tumor-protective effect of the recruited myeloid BMDCs has been attributed to their ability to support tumor vasculature after irradiation in a paracrine manner—analogous to that described for radiation-naive tumors. However, the contributions of specific provascular myeloid BMDC populations, including M2-type macrophages, Tie2 monocytes and Gr-1 monocytes, or neutrophils, and the signals that mediate their recruitment and local function are not well characterized.
Moreover, the status of tumor vasculature at certain post-radiation stages remains largely unclear. In general, the tolerance of tumor vessels to irradiation may play a dual role in radiotherapy. A stable vasculature is required to maintain the blood perfusion necessary for cancer cell (re)oxygenation, and therefore radiosensitization, throughout the course of treatment, which is usually fractionated in the clinic. However, functional vessels and viable endothelial cells (ECs) are undesirable after any type of tumor irradiation because they might support the survival and growth of remaining cancer cell clonogens and thus promote the relapse. Despite the intense research on tumor oxygenation during irradiation, little is known about the dynamics of vascular changes and the mechanisms of neovascularization after radiation.
This commentary focuses on revascularization of tumors after non-curative radiotherapy, which is arguably the least understood contributor to tumor regrowth post-radiation. In particular, we address the unanswered question regarding the source of neovessels in relapsing tumors. Many tumor-associated ECs are undoubtedly killed or at least deprived of proliferative capacity by high-dose irradiation. But are those ECs that survive still capable of reestablishing a tumor vasculature during post-radiation recurrence? Or do other players (eg, recruited BMDCs) become more important? To our knowledge, there is no consensus in the literature on this point.
Some researchers proposed that local tumor irradiation at a single dose of 15–20 Gy or higher can "sterilize" sufficient ECs inside and around the tumor to abrogate the growth and sprouting of irradiated vessels (angiogenesis), thereby forcing the tumor to rely on vasculogenesis by infiltrating cells. Indeed, because bone marrow–resident cells or circulating BMDCs receive very little exposure to radiation during tumor treatment, it is reasonable to expect that the recruitment and further incorporation of these cells in tumor vessels would be much more substantial post-radiation vs radiation-naive tumors. If supported by compelling data, this attractive hypothesis would also reconcile an unresolved yet controversial issue in the literature about whether gross tumor response to radiation is associated with vascular damage. Therefore, the influx of bone marrow–derived vascular precursors to tumors during the regrowth stage post-radiation, when additional cells are necessary for building new vessels, has recently been investigated. However, neither study could detect any substantial incorporation of BMDCs within the vessels of tumors regrowing post-radiation. Thus, BMDC-based vasculogenesis is not a major contributor to new vessel formation in irradiated tumors. An obvious alternative mechanism is post-radiation angiogenesis, provided local ECs survive and remain functional.
Is there any proof in the literature to support this mechanism? To address this question, we summarize below and in Table 1, the previous preclinical observations, and propose a model reconstructing the dynamics of events in tumor-associated ECs and vasculature in general after a single high dose (approximately 20 Gy) of local gamma- or x-ray irradiation. Such non-curative treatments have been widely used in animal studies and allow a better separation and understanding of post-radiation effects than fractionated irradiation regimens. This analysis is particularly timely because therapies using a single dose or a few large fractions of radiation are being increasingly tested in the clinic (eg, stereotactic body/ablative radiotherapy or radiosurgery). Although no specific data exist, it has been postulated that such irradiation induces more damage to tumor vasculature than conventional fractionated radiotherapy, which provides a crucial therapeutic benefit. The available data are fairly incomplete and inconsistent. Most studies have focused on early vascular effects, and the late post-radiation stages have been less explored. Moreover, the older studies lacked a specific marker for EC staining, and the more recent reports rarely evaluated ECs and vessel structure and function simultaneously. Clearly, there is no experimental consensus on the question of revascularization after radiation, and a logical conceptual framework would help direct future work in this area.
We propose such a framework, in which the tumor vascular response to irradiation occurs in four stages, which approximately corresponds to the phases of tumor size changes (Figure 1).
(Enlarge Image)
Figure 1.
Proposed model of tumor growth and corresponding changes in endothelial cell/vessel status after single-dose local irradiation (R). After irradiation (approximately 20 Gy), tumors normally continue to enlarge for a few days, then shrink (depicted) or become stable in size (not shown), and then they start to regrow. The time scale varies for different tumors, but the whole span is typically a few weeks. We have divided the post-radiation events into four different stages (I–IV), including two waves of the vessel-rescuing recruitment of myelomonocytes. Note that angiogenesis is required in stage IV only. EC = endothelial cell.
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