Low Doses of Ionizing Radiation Promote Tumor Growth and Metastasis by Enhancing Angiogenesis (Blood Vessel Formation)

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abnormal vasculature, angiogenesis, blood vessels, breast cancer, breast cancer mestastasis, cancer, cancer spread, cancer spreading, cancer treatment, dangers of ionizing radiation, dangers of nuclear, dangers of radiation therapy, leukemia, low dose ionizing radiation, low doses of IR, nuclear energy, nuclear power, radiology, tumors, tumours

Not only can low level ionizing radiation induce mutations leading to cancer, but it can cause existing cancer both to grow and to spread to other parts of the body!

“Metastasis, or metastatic disease, is the spread of a cancer from one organ to another“. http://en.wikipedia.org/wiki/Metastasis

“Tumor metastasis formation: interactions with blood vessels. (A) Small primary tumors (< 2 mm) remain avascular. After that, (B) tumor cells invade the basement membrane and produce angiogenic factors, promoting the (C) angiogenic switch, which allows the expansion of the primary tumor. (D) The new blood vessels provide a route of entry into the bloodstream and the tumor cells circulate until they die or (E) attach specifically to ECs in the vessels (usually venules) of downstream organs. (F) The tumor cells extravasate through the vessel wall and then (G) migrate to sites proximal to arterioles, where their growth is enhanced. (H) Micrometastasis can remain dormant for extended time periods, during which angiogenesis is suppressed. (I) Initiation of angiogenesis at the secondary site releases the metastatic colonies from dormancy and allows rapid growth. ” (Figure 14, p. 39, Vala, 2011) (Emphasis added) http://repositorio.ul.pt/bitstream/10451/4625/1/ulsd061477_td_Ines_Oliveira.pdf

From Vala, et. al. (2010):
“…recent evidence suggests that doses of ionizing radiation (IR) delivered inside the tumor target volume, during fractionated radiotherapy, can promote tumor invasion and metastasis. Furthermore, the tissues that surround the tumor area are also exposed to low doses of IR that are lower than those delivered inside the tumor mass, because external radiotherapy is delivered to the tumor through multiple radiation beams, in order to prevent damage of organs at risk… Using murine experimental models of leukemia and orthotopic breast cancer, we show that low-dose IR promotes tumor growth and metastasis… These findings demonstrate a new mechanism to the understanding of the potential pro-metastatic effect of IR …” Sofia Vala I, Martins LR, Imaizumi N, Nunes RJ, Rino J, et al. (2010) “Low Doses of Ionizing Radiation Promote Tumor Growth and Metastasis by Enhancing Angiogenesis“. PLoS ONE 5(6): e11222. doi:10.1371/journal.pone.0011222 (Emphasis added; Entire article below)

What is Angiogenesis? “Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels. This is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. The essential role of angiogenesis in tumor growth was first proposed in 1971 by Judah Folkman, who described tumors as ‘hot and bloody.“. http://en.wikipedia.org/wiki/Angiogenesis (Emphasis added)

Apoptosis – cell death – can be a good thing when dealing with ionizing radiation. Apoptosis may be induced “if damage is extensive and repair efforts fail: “The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of biochemical factors. Part of this pathway includes alpha-interferon and beta-interferon, which induce transcription of the p53 gene, resulting in the increase of p53 protein level and enhancement of cancer cell-apoptosis. p53 prevents the cell from replicating by stopping the cell cycle at G1, or interphase, to give the cell time to repair, however it will induce apoptosis if damage is extensive and repair efforts fail. Any disruption to the regulation of the p53 or interferon genes will result in impaired apoptosis and the possible formation of tumors.” [2] http://en.wikipedia.org/wiki/Apoptosis

Vala (2011) explains that “Tumors, as normal tissues, require an adequate supply of oxygen and nutrients, and an effective way to remove waste products ” As such, “solid tumor progression beyond a volume of approximately 1‐2 mm2 requires angiogenesis“(Nussenbaum and Herman, 2010, referenced in Vala, 2011, p. 35). However, “Tumor blood vessels are architecturally different from normal blood vessels, as they are irregularly shaped, dilated, tortuous, and can have dead ends” (Bergers and Benjamin, 2003, referenced in Vala, 2011, p. 35)

“Contrast between normal and tumor vasculature. (A, B) Scanning electron microscopic imaging of rat vascular casts showing (A) a normal microvasculature with organized arrangement of arterioles, capillaries, and venules, versus (B) a tumor microvasculature, with disorganized and lack of conventional hierarchy of blood vessels where arterioles, capillaries, and venules are not identifiable as such. (A’, B’) Diagram comparing the structure and close EC association of pericytes in a normal capillary (A’) versus a loosely association in tumor vasculature (B’). (A, B) Adapted (McDonald and Choyke, 2003). (A’, B’) Adapted and modified (Morikawa et al., 2002)” (Vala, 2011, Figure 12 p. 35) http://repositorio.ul.pt/bitstream/10451/4625/1/ulsd061477_td_Ines_Oliveira.pdf

According to Carmeliet and Jain (2000), as referenced in Vala (2011) “cancer is a clear example of a pathology characterized by an excessive angiogenesis, creating structurally and functionally abnormal vessels, highly disorganized, tortuous, dilated and excessively branched“. Some examples of angiogenesis-dependent diseases include cancer and metastasis, infectious diseases, auto‐immune disorders, DiGeorge syndrome, Cavernous hemangioma, Diabetic retinopathy, Age‐related macular degeneration, Endometriosis, Ovarian hyperstimulation, Ovarian cysts, Synovitis Osteomyelitis, Psoriasis Scar keloids (Vala, 2011, pp. 33-34, who says to see Carmeliet, 2005, for a complete list). http://repositorio.ul.pt/bitstream/10451/4625/1/ulsd061477_td_Ines_Oliveira.pdf

“The angiogenic switch seems to result mainly from the action of mutated oncogenes (e.g. c‐myc, Ras family, HER2) and tumor suppressor genes (e.g. p53, BRACA1/2, APC) that deregulate the angiogenic balance by promoting the disproportionate expression of angiogenic factors (in favor of angiogenic stimulators) (Bergers and Benjamin, 2003). In this process, hypoxia plays also an important role. Tumor progression associated to a dysfunctional vasculature leads to an insufficient oxygen supply to the tumorigenic tissue, causing the induction of HIFs and, consequently, neovessels formation (Dewhirst et al., 2008)… Although most of the studies regarding tumor angiogenesis are related to the progression of solid tumors, the angiogenic process has also been associated to a higher destructive potential and poor prognosis in a subset of hematological diseases, such as acute leukemia and multiple myeloma (Moehler et al., 2003). There are, however, some tumors that do not required angiogenesis or, in parallel, use different mechanisms (reviewed in Auguste et al.,2005). Astrocytomas are an example of brain tumors that acquire their blood supply by co‐option…“(Vala, 2011, p.36) (Emphasis added)

Lest anyone think that this radiation-induced angiogenesis could be a good thing: “Therefore, according to our findings low‐dose IR induces angiogenesis in vivo but, there is no evidence that it produces therapeutic angiogenesis in ischemic disease patients.“(Vala, 2011, p. xiii)
One might guess that it is unhelpful for ischemic disease, in part, because the radiation-induced angiogenesis is abnormal. On p. 181, Vala notes that “treatment with IR involves the risks of genetic damage and radiation-induced carinogenesis.” [3]

“Our observations provide novel insights into the biological effects of low‐dose IR relevant to tumor biology, which may serve as basis for the prevention of possible tumor‐promoting effects of current radiotherapy protocols.” (Vala, 2011, p. xiii)

For x-rays and gamma rays the Gy, Gray, is equivalent to Sv, Sievert.













Underline-Highlight Emphasis added; Original pdf is here: http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0011222&representation=PDF

While for x-rays and gamma rays the Gy, Gray, is equivalent to Sv, Sievert, for alpha radiation there is an "accepted" weighting factor of 20, meaning that, in theory, 1/20th of the amount of alpha should cause the same effect. And, 1 Gy is 20 Sv for alpha. However, this appears false because the alpha radiation is both more densely damaging and stays in the body for a life-time (half-life in the body of 20 to 50 years for plutonium and americium). So, it seems that the impact should be 20 times the person’s remaining lifetime or over 1000 times as bad. The impacts of alpha radiation are distinct from gamma and x-rays, since the damage to DNA is more severe; more dense; more localized, and hence harder to repair.

Dr. Vala and most of the authors are based in Portugal. Portugal has no nuclear energy. http://en.wikipedia.org/wiki/Nuclear_energy_in_Portugal

Notes-References

[1] “UNIVERSIDADE DE LISBOA FACULDADE DE CIÊNCIAS
DEPARTAMENTO DE BIOLOGIA VEGETAL
THE EFFECTS OF LOW­DOSE IONIZING RADIATION ON ANGIOGENESIS
INÊS SOFIA BATISTA VALA SILVA DE OLIVEIRA
DOUTORAMENTO EM BIOLOGIA (BIOLOGIA CELULAR)
2011” http://repositorio.ul.pt/bitstream/10451/4625/1/ulsd061477_td_Ines_Oliveira.pdf

[2] Problems of defects in Apoptosis:
“Implication in disease

Defective pathways
The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood. As a pathway is more or less sequential in nature, it is a victim of causality; removing or modifying one component leads to an effect in another. In a living organism, this can have disastrous effects, often in the form of disease or disorder. A discussion of every disease caused by modification of the various apoptotic pathways would be impractical, but the concept overlying each one is the same: The normal functioning of the pathway has been disrupted in such a way as to impair the ability of the cell to undergo normal apoptosis. This results in a cell that lives past its "use-by-date" and is able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of the cell's becoming cancerous or diseased.

A recently described example of this concept in action can be seen in the development of a lung cancer called NCI-H460. The X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9, and suppress the activity of apoptotic activator cytochrome c, therefore overexpression leads to a decrease in the amount of proapoptotic agonists. As a consequence, the balance of anti-apoptotic and proapoptotic effectors is upset in favour of the former, and the damaged cells continue to replicate despite being directed to die.

The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of biochemical factors. Part of this pathway includes alpha-interferon and beta-interferon, which induce transcription of the p53 gene, resulting in the increase of p53 protein level and enhancement of cancer cell-apoptosis. p53 prevents the cell from replicating by stopping the cell cycle at G1, or interphase, to give the cell time to repair, however it will induce apoptosis if damage is extensive and repair efforts fail. Any disruption to the regulation of the p53 or interferon genes will result in impaired apoptosis and the possible formation of tumors.

Inhibition
Inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections. It was originally believed that the associated accumulation of cells was due to an increase in cellular proliferation, but it is now known that it is also due to a decrease in cell death. The most common of these diseases is cancer, the disease of excessive cellular proliferation, which is often characterized by an overexpression of IAP family members. As a result, the malignant cells experience an abnormal response to apoptosis induction: Cycle-regulating genes (such as p53, ras or c-myc) are mutated or inactivated in diseased cells, and further genes (such as bcl-2) also modify their expression in tumors.

HeLa cell
Apoptosis in HeLa cells is inhibited by proteins produced by the cell; these inhibitory proteins target retinoblastoma tumor-suppressing proteins. These tumor-suppressing proteins regulate the cell cycle, but are rendered inactive when bound to an inhibitory protein. HPV E6 and E7 are inhibitory proteins expressed by the human papillomavirus, HPV being responsible for the formation of the cervical tumor from which HeLa cells are derived. HPV E6 causes p53, which regulates the cell cycle, to become inactive. HPV E7 binds to retinoblastoma tumor suppressing proteins and limits its ability to control cell division. These two inhibitory proteins are partially responsible for HeLa cells' immortality by inhibiting apoptosis to occur. CDV (Canine Distemper Virus) is able to induce apoptosis despite the presence of these inhibitory proteins. This is an important oncolytic property of CDV: this virus is capable of killing canine lymphoma cells. Oncoproteins E6 and E7 still leave p53 inactive, but they are not able to avoid the activation of caspases induced from the stress of viral infection. These oncolytic properties provided a promising link between CDV and lymphoma apoptosis, which can lead to development of alternative treatment methods for both canine lymphoma and human non-Hodgkin lymphoma. Defects in the cell cycle are thought to be responsible for the resistance to chemotherapy or radiation by certain tumor cells, so a virus that can induce apoptosis despite defects in the cell cycle is useful for cancer treatment.”
http://en.wikipedia.org/wiki/Apoptosis

[3] On p. 181, after stating all of the reasons that IR is dangerous and bad: “risks of genetic damage and radiation-induced carcinogenesis“, Vala (2011) states that “the potential toxicological effects of low doses of IR are being assessed in collaboration with Vivotecnia (Spain)”
No accounting for folly! It would be interesting to see what the funding for this dissertation was. Too bad! It’s a really nicely done dissertation, to end with such a note.