Radiotherapy (RT), besides cancer cells, also affects the tumor microenvironment (TME): tumor blood vessels and cells of the immune system. It damages endothelial cells and causes radiation-induced inflammation. Damaged vessels inhibit the infiltration of CD8+ T lymphocytes into tumors, and immunosuppressive pathways are activated. They lead to the accumulation of radioresistant suppressor cells, including tumor-associated macrophages (TAMs) with the M2 phenotype, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). The area of tumor hypoxia increases. Hypoxia reduces oxygen-dependent DNA damage and weakens the anti-cancer RT effect. It activates the formation of new blood vessels and leads to cancer relapse after irradiation. Irradiation may also activate the immune response through immunogenic cell death induction. This leads to the “in situ” vaccination effect. In this article, we review how changes in the TME affect radiation-induced anticancer efficacy. There is a very delicate balance between the activation of the immune system and the immunosuppression induced by RT. The effects of RT doses on immune system reactions and also on tumor vascularization remain unclear. A better understanding of these interactions will contribute to the optimization of RT treatment, which may prevent the recurrence of cancer.

https://www.mdpi.com/1422-0067/20/13/3212/pdf

Tumor Microenvironment as A "Game Changer" in Cancer Radiotherapy.

DNA double-strand breaks arise accidentally upon exposure of DNA to radiation and chemicals or result from faulty DNA metabolic processes. DNA breaks can also be introduced in a programmed manner, such as during the maturation of the immune system, meiosis, or cancer chemo- or radiotherapy. Cells have developed a variety of repair pathways, which are fine-tuned to the specific needs of a cell. Accordingly, vegetative cells employ mechanisms that restore the integrity of broken DNA with the highest efficiency at the lowest cost of mutagenesis. In contrast, meiotic cells or developing lymphocytes exploit DNA breakage to generate diversity. Here, we review the main pathways of eukaryotic DNA double-strand break repair with the focus on homologous recombination and its various subpathways. We highlight the differences between homologous recombination and end-joining mechanisms including non-homologous end-joining and microhomology-mediated end-joining and offer insights into how these pathways are regulated. Finally, we introduce noncanonical functions of the recombination proteins, in particular during DNA replication stress.

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Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes.

Metformin is a widely used drug in today's prescriptions by physicians due to its specific effects in treating and curing type II diabetes. Diabetes is a common disease that may occur throughout human life, and can increase the likelihood of the occurrence of various types of cancer, such as colon, rectum, pancreas and liver cancers, compared to non-diabetic patients. Metformin inhibits mTOR activity by activating ATM (ataxia telangiectasia mutated) and LKB1 (liver kinase B1) and then adenosine monophosphate-activated kinase (AMPK), and thus prevents protein synthesis and cell growth. Metformin can activate p53 by activating AMPK and thereby ultimately stop the cell cycle. Given the potential of metformin in the treatment of cancer, it can be used in radiotherapy, chemotherapy and to improve the response to treatment in androgen derivatives (ADT), and also, according to available evidence, metformin can also be used to prevent various types of cancers. Generally, metformin can: 1) reduce the incidence of cancers, 2) reduce the mortality from cancers, 3) increase the response to treatment in cancer cells when using radiotherapy and chemotherapy, 4) optimize tumor movement and reduce the malignancy, 5) reduce the likelihood of relapse, and 6) reduce the damaging effects of ADT. Therefore, this drug can be used as a complementary therapeutic agent for cancer treatment and prevention. In this review, we have summarized the data from various experimental and clinical studies and highlight the possible potential effects of metformin on cancer therapeutic responses.

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The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances

/pdf/main-steps-in-dna-double-strand-break-repair-12q0m642d7.pdf

Main steps in DNA double-strand break repair

Liposomes have been well established as an effective drug delivery system, due to simplicity of their preparation and unique characteristics. However conventional liposomes are unsuitable for the on-demand content release, which limits their therapeutic utility. Here we report X-ray-triggerable liposomes incorporating gold nanoparticles and photosensitizer verteporfin. The 6 MeV X-ray radiation induces verteporfin to produce singlet oxygen, which destabilises the liposomal membrane and causes the release of cargos from the liposomal cavity. This triggering strategy is demonstrated by the efficiency of gene silencing in vitro and increased effectiveness of chemotherapy in vivo. Our work indicates the feasibility of a combinatorial treatment and possible synergistic effects in the course of standard radiotherapy combined with chemotherapy delivered via X-ray-triggered liposomes. Importantly, our X-ray-mediated liposome release strategy offers prospects for deep tissue photodynamic therapy, by removing its depth limitation.

/pdf/controlled-gene-and-drug-release-from-a-liposomal-delivery-3dw6ujoddg.pdf

Controlled gene and drug release from a liposomal delivery platform triggered by X-ray radiation.

Cancer is a class of diseases characterized by uncontrolled cell growth and has the ability to spread or metastasize throughout the body. In recent years, remarkable progress has been made towards the understanding of proposed hallmarks of cancer development, care and treatment modalities. Radiation therapy or radiotherapy is an important and integral component of cancer management, mostly conferring a survival benefit. Radiation therapy destroys cancer by depositing high-energy radiation on the cancer tissues. Over the years, radiation therapy has been driven by constant technological advances and approximately 50% of all patients with localized malignant tumors are treated with radiation at some point in the course of their disease. In radiation oncology, research and development in the last three decades has led to considerable improvement in our understanding of the differential responses of normal and cancer cells. The biological effectiveness of radiation depends on the linear energy transfer (LET), total dose, number of fractions and radiosensitivity of the targeted cells or tissues. Radiation can either directly or indirectly (by producing free radicals) damages the genome of the cell. This has been challenged in recent years by a newly identified phenomenon known as radiation induced bystander effect (RIBE). In RIBE, the non-irradiated cells adjacent to or located far from the irradiated cells/tissues demonstrate similar responses to that of the directly irradiated cells. Understanding the cancer cell responses during the fractions or after the course of irradiation will lead to improvements in therapeutic efficacy and potentially, benefitting a significant proportion of cancer patients. In this review, the clinical implications of radiation induced direct and bystander effects on the cancer cell are discussed.

/pdf/biological-response-of-cancer-cells-to-radiation-treatment-18f76d6ikt.pdf

Biological response of cancer cells to radiation treatment.

The purpose of the study was to investigate whether fecal occult blood test (FOBT) home-delivery and individual education or combined with family education increases FOBT uptake rates in Singapore. This is a randomized controlled intervention study of Singaporean residents aged 50 years and above, conducted in May 2012 till May 2013. Eligible individuals in randomly selected households were screened, and one member was randomly selected and allocated to one of the four arms: Group A (individual and family education, FOBT kits provided), Group B (individual education only, FOBT kits provided), Group C (no education, FOBT kits provided) and Group D (no education or FOBT kits provided). Overall response rate was 74.7 %. The FOBT return rates for groups A, B, C and D were 24.5 % [CI 16.2–34.4 %], 25.3 % [CI 16.4–36.0 %], 10.7 % [CI 4.7–19.9 %] and 2.2 % [CI 0.3–7.7 %], respectively. Respondents who were provided education and home-delivered FOBT kits were 15 times more likely to return FOBT kits [Group A: OR 15.0 (3.4–66.2); Group B: OR 15.5 (3.5–68.8)] and those provided with home-delivered FOBT without education were five times more likely to return FOBT kits [Group C: OR 5.8 (1.2–28.3)] than those without education and FOBT kits (Group D). There was no significant difference in return of FOBT kits whether education was provided to subject with or without a family member. Home delivery of FOBT kits increased FOBT return rates and individual education combined with home-delivered FOBT increased FOBT return rates even further. However, additional combination with family education did not increase FOBT rates further.

The effect of test kit provision, and individual and family education on the uptake rates of fecal occult blood test in an Asian population: a randomized controlled trial

Kheng-Wei Yeoh

Papers

Biological response of cancer cells to radiation treatment.

The effect of test kit provision, and individual and family education on the uptake rates of fecal occult blood test in an Asian population: a randomized controlled trial