What is inflammation? How is it related to cancer?

Inflammation, inflammation, inflammatory reaction or, as it is commonly known, inflammation, is the entirety of the physiological responses of tissues supplied by blood vessels to any form of injury, whether a living or nonliving foreign agent or internal/external tissue damage. Inflammation derives from the Latin term meaning “to set on fire”, and its purpose is to allow cells of the immune system to be recruited to the site of attack and destroy the aggressor.

The immune system response may be cellular, humoral (fluid-related) or vascular (blood-vessel-related).

Although inflammation is normally a pathological condition, the inflammatory reaction is a physiological response by the body. Although the everyday term for inflammation is used for this reaction, it is also frequently used for abscesses, so the term inflammatory reaction is more appropriate. Inflammation forms the pathological basis of diseases.

Symptoms of inflammation

There are 5 main general signs of inflammation:

1. Redness
2. Pain
3. A localized rise in temperature
4. Swelling and
5. Loss of function

Cancer and inflammation

Inflammation is also among the 10 hallmarks of cancer. The tumor environment contains not only cancer cells but also immune system cells associated with inflammation; this environment is called the tumor microenvironment . By increasing growth factors and enzymes, these cells create an environment supporting new blood vessel formation and cancer spread. They also produce reactive oxygen radicals, causing DNA damage and cancer formation.

Inflammation lays the groundwork for cancer development and supports every stage of tumor formation. Cancer cells, surrounding connective tissue and inflammatory immune cells engage in well-organized reciprocal interactions to form an inflammatory tumor microenvironment (TME). Cells within the TME have extremely high plasticity and continuously alter their phenotypic and functional characteristics. Defining the fundamental rules governing molecular and cellular mechanisms of tumor-promoting inflammation will be necessary to develop more effective anticancer treatments.

Cancer-associated inflammation can also be triggered at different times during tumor development. To disrupt the roles and mechanisms of inflammation and cancer, it is therefore important to understand how inflammation in cancer first starts and is maintained, in terms of both timing and stimulus (Figure 1).

Figure 1: A) Cancer-associated inflammation may be triggered at different times during tumor development. In the form of autoimmunity or infection, it may precede carcinogenesis , be triggered by cancer cells, or be triggered by anticancer treatment. B) Many factors, whether intracellular, host-cell-related or environmental, can cause tumor-associated inflammation in different tumor types.

Chronic inflammation, infection and autoimmunity before tumor formation

Approximately %15-20of all cancer cases are preceded by infection, chronic inflammation or autoimmunity in the same tissue or organ site. In such cases, cancer-promoting inflammation is triggered long before tumor formation.

There are also various environmental factors that entirely or partly predispose to and promote cancer by triggering chronic inflammation, sometimes low-grade and sometimes severe. Inflammation may then occur before or alongside tumor development. In relation to the host cell, these factors may be systemic or site- and organ-specific. For example, tobacco smoke primarily causes lung and respiratory tract inflammation, promoting lung cancer and mesothelioma . In contrast, low-grade inflammation caused by obesity and hyperglycemia (high blood sugar) is generally systemic and may increase the risk of many different cancers, including liver, pancreatic, colon and breast cancer. Type-II diabetes, previously considered an independent cancer risk factor, may be viewed as part of obesity-related inflammation and tissue damage.

Tumor-elicited inflammation

However, the majority of cancers do not develop before long-standing chronic inflammation. For example, although inflammatory bowel disease predisposes to colitis-associated cancer, only about %2 of colorectal cancers have preceding intestinal inflammation. In addition, suppressing inflammatory responses in animal experiments inhibited tumor growth and progression even in apparently noninflammatory cancers.

The observation that cancers previously described as “noninflammatory” recruit immune cells and increase expression of inflammatory mediators to support tumor growth and remodel their TME in their own favor led to the term “tumor-elicited inflammation” (TEI).

However, triggers of TEI may differ in microbe-rich and sterile tumors. In colitis-associated cancer, for example, oncogene-driven disruption of the protective intestinal barrier at the tumor-formation site leads to translocation of commensal bacteria and bacterial products, which are recognized by tumor-associated myeloid cells to trigger IL-23 production and IL-23-dependent TEI.

In contrast, in tumors unrelated to mucosal surfaces, the initial inflammatory trigger may arise from sensing oncogenic transformation, metabolic changes, cell death or hypoxia.

Treatment-induced inflammation in cancer

Another type is treatment-induced inflammation, which develops in response to various anticancer treatments, including chemotherapy and radiotherapy, and more recently to immune infiltration caused by various biological treatments or immunotherapies. Activation of the immune system within the tumor after treatment is the fundamental rationale of current immunotherapies. This process may also be beneficial for stimulating antitumor immune responses that work in combination with standard treatments.

In some cases, release of damage-associated molecular patterns, such as ATP and High Mobility Group Protein 1 (High Mobility Group Box 1), from attacked and dying tumor cells can trigger production of IL-1α and other cytokines that stimulate the immune system. Together with increased release of tumor neoantigens, this may trigger and maintain de novo antitumor T-cell responses or lead to immunosuppression. The net outcome, however, will depend on how the relevant cytotoxic regimens or radiotherapies affect activation and function of anticancer immune cells.

Many tumors also have deficient apoptotic (programmed) cell death, so cell death through necrosis may stimulate the immune system. For example, necroptotic death of tumor cells may trigger local and abscopal antitumor immunity even against antigens shared between dying and remaining tumor cells.

In many cases, partial tumor destruction by treatment and release of dead-cell material will also have immunosuppressive effects. This stimulates an inflammatory response resembling injury to normal tissue, followed by wound healing and tissue repair. Here, recognition of dying tumor cells stimulates cytokine and growth factor production by TME cells and further recruitment of these cells. These growth factors acting from outside the cell may generally function as anti-cell-death signals, reducing treatment effectiveness.

Because cancer stem cells are less proliferative and less metabolically active, they are less sensitive to many forms of chemotherapy and radiotherapy. Increased recruitment of myeloid cells and their release of pyrimidine nucleotides confer resistance to gemcitabine in pancreatic cancers, exemplifying a nonimmune, metabolic role of inflammatory cells in treatment resistance.

Another mechanism is that chemotherapies cause normal tissue damage, particularly in the intestine, translocation of inflammatory microbial products and activation of systemic inflammation. This further promotes tumors in myelodysplastic syndrome and various metastatic cancers in which microbial products accelerate metastasis.

In conclusion, treatment-induced inflammation develops only after treatment but may play an important role in determining treatment effectiveness or resistance. In this context, identifying the precise signals triggering inflammation during tumor development will undoubtedly help achieve a better and broader understanding of how tumor development shapes the TME.

Sources and stimuli for inducing inflammation during tumor formation

Various mechanisms explain how initial inflammatory responses may be induced and the relevant causes and stimuli (Figure 1B).

One hallmark of cancer is loss of cell-intrinsic tumor suppressor functions. Among the most commonly mutated tumor suppressors, one encoding the p53 protein is Tp53. The P53 protein has diverse functions in regulating cellular homeostasis, including transcriptional antagonism with Nuclear Factor-κB (NF-κB), a major positive regulator of inflammation. Since NF-κB-activating signals are always present in the TME and even in normal tissue, loss of functional p53 increases expression of NF-κB-dependent inflammatory genes. This increases tumor progression and metastasis in colorectal cancer. Loss of tumor suppressors may also impair proper DNA repair and accelerate DNA damage, triggering DNA-damage-associated inflammatory pathways.

If tumor development and progression are initially preceded by a pathogen such as HPV (human papillomavirus), recognition of persistent pathogens will of course promote different inflammatory responses. Recognition of cancer-causing pathogens through “classical” receptors that recognize these conserved molecular patterns is one of the simplest examples of triggering innate inflammatory responses.

Another paradigm is that many cancer types can be triggered by commensal microbiota, either through microorganisms adhering to cancer cells or through distant release of microbial metabolites that activate inflammation. These microorganisms and microbial products may even travel with tumors to metastatic sites and become a source of inflammation in metastases.

Although the source and/or trigger of inflammation in cancer varies, its induction appears always closely associated with the emergence of factors essential to the oncogenic process: alterations in oncogenes and tumor suppressors, infections in microbe-driven cancers, or impaired barrier function due to transformation-induced loss of tissue organization. Because inflammation is wired to be induced during responses to loss of tissue homeostasis, its induction is “preprogrammed” in the genetic and transcriptional programs required for oncogenic transformation and therefore in many circumstances.

In conclusion

Studies of mechanisms of protumorigenic inflammatory pathways in cancer have revealed that tumors exploit these pathways, which evolved to mediate immunity against infection and support tissue homeostasis, for their own benefit. Induction of inflammation in the TME may follow different timelines. It may occur before or after tumor formation begins. It may also remain silent until late stages of metastasis or treatment resistance.

There are several different stimuli inducing inflammation in tumors. Examples include carcinogenic microorganisms, environmental factors and obesity-associated low-grade inflammation, as well as commensal microorganisms associated with epithelial barrier disruption.

As modern cancer treatments continue to expand, including various treatments based directly on immune cells, such as checkpoint immunotherapies, vaccines and CAR T cells, uncovering the role of immune and inflammatory pathways in treatment resistance will be essential. Given that inflammation may play a role at every stage of tumor development, future research will also reveal molecular and cellular mechanisms of inflammation and immune cells, particularly in early tumor formation and metastasis. This will enable precision treatments for many cancer types.