Cancer, one of the most serious public health problems in today’s world, has been precisely described as “The Emperor of All Maladies”. ^[1] According to the Global Cancer Observatory, approximately 19.3 million new cancer cases occurred in 2020, leading to 10 million deaths. In addition, the burden of cancer is expected to increase by around 60% in the next two decades, reaching approximately 30 million new cases globally by 2040. ^[2]
According to the European Cancer Information System’s (ECIS) predictions, cancer incidents are estimated to increase from 2.68 million (2020) to 3.24 million cases in 2040, a 20.96% raise caused due to demographic change.^[3] The cancer burden is predicted to increase by approximately 60% over the next two decades, further straining health systems, people and communities.^[4] Within the context of Greece, the World Health Organization's data for 2020 revealed nearly 65,000 new cancer cases, of which over 33,000 were fatal.^[5]

In general, approximately 19-20 million people are diagnosed with cancer worldwide each year, with solid tumors accounting for approximately 90% of adult human cancers and affecting various parts of the body. ^[6]

Statistics have revealed that in children, solid tumors make up about 40% of all cancers. The most common and aggressive type of solid tumor found in children is a brain tumor. ^[6]

It all starts with a single mutation. The DNA strand is now compromised. A mutation/duplication of a single nucleotide or a nucleotide depletion disrupts the DNA sequence. This change in the genome is irreversible and can lead to the transformation of a normal cell into a tumor cell. Cancer can spread to nearby tissues or remote organs through the lymph system and bloodstream. ^[6]

Solid tumors contain abnormal and heterotypic cells that communicate through tight and gap junctions. In contrast with liquid tumors, as the cells multiply, they form a “mass” called a solid tumor and usually do not contain pockets of fluid, pus, air, or other substances. ^[6]

Solid tumors can be either non-cancerous (benign), pre-malignant (cells that have the potential to become malignant), or malignant (cancerous). The genomic background of pediatric tumors is different from that of adult tumors. The same tumor types tend to have completely different mutation profiles compared to their adult counterparts. Statistics have revealed that in children, solid tumors make up about 40% of all cancers. The most common and aggressive type of solid tumor found in children is a brain tumor.^[6]

Understanding that cancer, the emperor of all maladies, is nothing but the uncontrollable multiplication of normal cells, raises the question: How can we even beat a disease that is a distorted version of our normal selves? "We have only seen our monster more clearly and described his scales and fangs in new ways – ways that reveal a cancer cell to be a distorted version of our normal selves", said Harold Varmus, accepting his Nobel prize for the cellular origin of retroviral oncogenes in 1989. ^[7] The answer to that question is far from simple… Mukherjee, in his description of cancer as the emperor of all maladies, emphasizes that the idea of cancer cells simply being copies of who we are is not a metaphor. "We can rid ourselves of cancer," he concludes, "only as much as we can rid ourselves of the processes in our physiology that depend on growth – ageing, regeneration, healing, reproduction."^[1]


Numerous modalities for cancer treatment are currently in use, including:

Surgery

Excision of tumors is the most frequently employed form of cancer therapy. In recent years, combining it with other treatment modalities such as chemotherapy and radiation therapy has enhanced the effectiveness of surgery. Possible complications during surgery may be caused by the surgery itself, drugs used, and the patient's overall health. The more complex the surgery is, the greater the risk of side effects.

The most common side-effects include:
Bleeding
Blood clots
Damage to nearby tissues
Drug reactions
Damage to other organs
Pain
Infections
Slow recovery of other body functions ^[8]

Chemotherapy

The word "chemotherapy" ("chemo") is often used when referring to medicines or drugs that treat cancer. Traditional or standard chemotherapy uses drugs that are cytotoxic, with cisplatin being the most common drug in use. Chemotherapy not only kills fast-growing cancer cells, but also kills or slows the growth of healthy cells that grow and divide quickly. Examples are cells that line your mouth and intestines and those that cause your hair to grow.

Here are some of the more common side effects caused by chemotherapy:

Fatigue
Hair loss
Easy bruising and bleeding
Anemia (low red blood cell counts)
Nausea and vomiting
Appetite changes
Constipatio
Mouth, tongue, and throat problems such as sores and pain with swallowing
Peripheral neuropathy or other nerve problems, such as numbness, tingling, and pain
Skin and nail changes such as dry skin and color change
Urine and bladder changes and kidney problems
Weight changes
Chemo brain, which can affect concentration and focus
Mood changes
Changes in libido and sexual function
Fertility problems
Infection ^[9]

Hormone therapy

Hormone therapy is a cancer treatment that slows or stops the growth of cancer that uses hormones to grow. Hormone therapy is mainly used to treat prostate and breast cancer. Hormone therapy is most often used along with other cancer treatments. The types of treatment that the patient needs depend on the type of cancer, if it has spread and how far, if it uses hormones to grow and the presence of other health problems.

Men who get hormone therapy for prostate cancer might have these possible side effects:

Hot flashes
Decreased sexual desire
Erectile dysfunction (trouble getting an erection)
Bone loss and a higher risk for fractures
Fatigue
Weight gain (especially around the belly) with decreased muscle mass
Memory problems
Increased risk of other health problems

Women getting hormone therapy for breast or endometrial cancer might have these possible side effects:

Hot flashes
Vaginal discharge, dryness, or irritation
Decreased sexual desire
Fatigue
Nausea
Pain in muscles and joints
Bone loss and a higher risk for fractures
Higher risk of other types of cancer, stroke, blood clots, cataracts, and heart disease ^[10]

Immunotherapy

Immunotherapy is a type of cancer treatment that helps the immune system fight cancer. As part of its normal function, the immune system detects and destroys abnormal cells and most likely prevents or curbs the growth of many cancers. For instance, immune cells are sometimes found in and around tumors. These cells, called tumor-infiltrating lymphocytes or TILs, are a sign that the immune system is responding to the tumor. People whose tumors contain TILs often do better than people whose tumors don’t contain them. Even though the immune system can prevent or slow cancer growth, cancer cells have ways to avoid destruction by the immune system. For example, cancer cells may have genetic changes that make them less visible to the immune system or contain proteins on their surface that turn off immune cells.

Some of the most common types of immunotherapy include:

Immune checkpoint inhibitors, which are drugs that block immune checkpoints. These checkpoints are a normal part of the immune system and keep immune responses from being too strong. By blocking them, these drugs allow immune cells to respond more strongly to cancer.

T-cell transfer therapy, which is a treatment that boosts the natural ability of the T cells to fight cancer. In this treatment, immune cells are taken from the tumor. Those that are most active against cancer are selected or changed in the lab to better attack cancer cells, grown in large batches, and put back into the body through a needle in a vein.

Monoclonal antibodies, which are immune system proteins created in the lab that are designed to bind to specific targets on cancer cells. Some monoclonal antibodies mark cancer cells so that they will be better seen and destroyed by the immune system.
Some side effects are common with all types of immunotherapy:

fever
chills
weakness
dizziness
nausea or vomiting
muscle or joint aches
fatigue
headache
trouble breathing
low or high blood pressure

Other side effects might include:

swelling and weight gain from retaining fluid
heart palpitations
heart palpitations
diarrhea
infection
organ inflammation ^[11]

Radiation therapy (RT)

Radiation therapy (also called radiotherapy) is a cancer treatment that uses high doses of radiation to kill cancer cells and shrink tumors. At high doses, radiation therapy kills cancer cells or slows their growth by damaging their DNA. Cancer cells whose DNA is damaged beyond repair stop dividing or die. When the damaged cells die, they are broken down and removed by the body.

Radiation therapy does not kill cancer cells right away. It takes days or weeks of treatment before DNA is damaged enough for cancer cells to die. Then, cancer cells keep dying for weeks or months after radiation therapy ends.

Radiation not only kills or slows the growth of cancer cells, it can also affect nearby healthy cells. Damage to healthy cells can cause side effects.

Depending on the part of the body that is treated, some of the following side-effects might occur:

Fatigue
Hair loss
Memory or concentration problems
Nausea and vomiting
Skin changes
Headache
Blurry vision
Swelling (edema)
Tenderness
Mouth problems
Taste changes
Throat problems, such as trouble swallowing
Less active thyroid gland
Diarrhea
Sexual problems
Fertility problems
Urinary and bladder problems ^[12]

But how does PDT work?

The therapy depends on the dynamic interaction of molecules, called photosensitizers (PS), with light at specific wavelengths, and molecular oxygen, promoting the generation of reactive oxygen species (ROS), which are cytotoxic. ^[14] The PS molecule is administered topically or intravenous, until it selectively accumulates in the tumor tissue and subsequently it is exposed to light of an appropriate wavelength. The PS itself does not react with biomolecules; however, illumination transfers energy from light to molecular oxygen, to generate ROS, such as singlet oxygen (¹O₂), superoxide radical (O₂^•−), hydroxyl radical (HO^•), and hydrogen peroxide (H₂O₂). These cytotoxic photoproducts start a series of biochemical events, which induce damage and death of the target tissue. ^[15]

Do you want to dive even further?

After light absorption, the PS is transformed from its ground state (singlet state, ¹PS) to a short-lived, electronically excited singlet state (a few nanoseconds or less, ¹PS*). This excited state is very unstable and can decay to the ground state, losing the excess of energy through light emission (fluorescence) or heat production (internal conversion). However, the singlet state can undergo intersystem crossing and progress to a more stable, long-lived, electronically excited state (triplet state, ³PS*), through spin conversion of the electron in the higher-energy orbital. This excited state can decay to the ground state through light emission (phosphorescence) or undergo two kinds of reactions. The triplet state has a longer lifetime (up to tens of microseconds), which allows sufficient time for direct transfer of energy to molecular oxygen (O₂). This energy transfer step leads to the formation of singlet oxygen (¹O₂) and the fundamental state of the PS, called type II reaction. The singlet oxygen is extremely reactive and can interact with many biological substrates, inducing oxidative damage and ultimately cell death. The type I reaction can also occur if the excited state of the PS reacts directly with a substrate, such as cell membrane or a molecule, and undergoes hydrogen atom abstraction or electron transfer reactions, to yield free radicals and radical ions. These radicals react with molecular oxygen, producing ROS, such as O₂^•−, HO^•, and H₂O₂, which produce oxidative damage that can lead to biological lesions. ^[16]

A Jablonski diagram of the PDT action mechanism is summarized in the following figure.

THE BIG ‘‘BUT’’…

Perhaps the biggest limitation of using PDT to combat cancer is the light source, as visible light cannot adequately penetrate the human body. Red light is extinguished some 4–5 mm beneath the surface of the skin whereas ultraviolet hardly penetrates at all and blue barely 1 mm into tissue. ^[17] This implies that PDT is not a viable option for targeting cancers located deeply within the human body or tumors that have already metastasized extensively. So far, PDT is mainly used for the treatment of skin cancer or other types of cancers, located on or just below the skin's surface.

Bacteria Mediated Tumor Therapy has gained significant attention in the field of oncology due to bacteria’s remarkable properties, which include specific tumor-targeting abilities, high motility, immunogenicity, and their potential as carriers of therapeutic genes and drugs. Various bacterial strains have already exhibited promising outcomes in treating solid and metastatic tumors.

Synthetic biology techniques have enabled the precise control of therapeutic protein expression within engineered bacteria. Additionally, nanomaterials have been extensively employed to modify bacteria for specific purposes such as targeted drug delivery, photothermal therapy, magnetothermal therapy, and photodynamic therapy. These innovative approaches not only enhance the effectiveness of cancer treatments but also offer the potential for synergistic therapeutic interventions in the battle against cancer. ^[18]

IRIS is nothing else but a bacterial machine, created by us to perform bacteria mediated tumor therapy based on the principles of Photodynamic Therapy.


IRIS' Omne trium perfectum: PS, light, oxygen

Tumor sites are usually hypoxic, meaning that their environment is mostly anaerobic, allowing the growth of obligate and facultative anaerobic microorganisms. Cancer cells produce excessive amounts of nutrients and other factors because of their uncontrollable multiplication. Those big amounts of nutrients also support the growth of microorganisms in the tumor sites.

IRIS is based on E.Coli bacteria, a facultative anaerobic species of bacteria that can grow with or without the presence of oxygen. IRIS accumulates in the hypoxic tumor environment and uses the highly nutrient cancer environment to flourish and perform PDT to destroy cancer cells!

But how are all these integrated into one therapeutic solution?

Learn more on the of our project!

1. Mukherjee, S. (2011). The emperor of all maladies. Fourth Estate.
2. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available from: https://gco.iarc.fr/today , accessed [18 June, 2023].
3. “Estimated Number of New Cases in 2020, World, Both Sexes, All Ages.” Available from: https://gco.iarc.fr/today, accessed 18 Sept. 2023.
4. Cancer burden statistics and trends across Europe | ECIS. Available from: https://ecis.jrc.ec.europa.eu/, accessed [18 June, 2023].
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14. Correia, J.H.; Rodrigues, J.A.; Pimenta, S.; Dong, T.; Yang, Z. Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions. Pharmaceutics 2021, 13, 1332. https:// doi.org/10.3390/pharmaceutics13091332
15. Fitzgerald, F. Photodynamic Therapy (PDT): Principles, Mechanisms and Applications; Nova Science Publishers, Inc.: New York, NY, USA, 2017
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17. Ash, Caerwyn & Dubec, Michael & Donne, Kelvin & Bashford, Tim. (2017). Effect of wavelength and beam width on penetration in light-tissue interaction using computational methods. Lasers in Medical Science. 32. 10.1007/s10103-017-2317-4.
18. Liang S, Wang C, Shao Y, Wang Y, Xing D and Geng Z (2022), Recent advances in bacteria-mediated cancer therapy. Front. Bioeng. Biotechnol. 10:1026248. doi: 10.3389/fbioe.2022.1026248