Inflammation-cancer link is indirect and convoluted. Rather than inflammation per se, failure to resolve it is a common feature of early tumor development. In particular chronic inflammation (, ), specifically tumor-promoting inflammation is now considered a tumor-enabling characteristic ( ).
I. Explains inflammation is a process, not an outcome, and why the distinction matters.
II. Explains how the inflammatory process could either help or hinder cancer growth. Dysregulated (unresolved and/or inappropriate) helps while regulated inflammation hinders.
III. Shares some epidemiological data suggesting dysregulated inflammation could increase cancer risk.
IV. Explains how certain types of inflammation could hinder, even eliminate cancers, asshowed with his .
V. Shares some epidemiological data suggesting certain types of inflammation could reduce cancer risk.
VI. Shares some epidemiological data suggesting reducing inflammation could reduce cancer risk.
I. Inflammation Is A Process, Not An Outcome
Inflammation, a normal physiological process (), has been dealt a bad rap in popular culture where it’s usually used tacitly as synonymous with bad outcome when it’s actually a fundamental attribute of physiology, a dynamic immunological process that appears designed to
- Manifest itself in response to homeostatic perturbation in a given tissue,
- Help resolve such perturbation and help restore the tissue to its former homeostasis, and
- Itself disappear.
The last clearly indicates inflammation is normally a self-limiting process with a finite end (, , ). For thousands of years, starting with its first apparent recorded report by the Roman encyclopedist, , inflammation was described using its cardinal features, redness (rubor), heat (calor), swelling (tumor) and pain (dolor) until 1852 when added loss of function (functio laesa, injured function) ( ). Given its characteristic features, infections are stereotypical triggers of the inflammatory process.
Mild or severe, short-lived (acute) or prolonged (chronic), it’s a process whose features, course and consequences vary vastly in scope and length, and are contingent on the triggers that initiate it and the constraints of the tissues where it occurs. For example, being encased by the bony skull renders the soft brain tissue particularly ill-suited to effectively deal with some of inflammation’s characteristic consequences such as greater than normal influx of blood-derived cells and fluid, especially when it presents abruptly as an intense and relentless process as happens in.
Unfortunately, even in biomedicine, the word inflammation is also often misused to describe any number and variety of undesirable or adverse outcomes when it is instead a process. Such distortion of the fundamental framework ends up distorting experimental goals and design so no surprise if confusing results ensue.
Another problem of epidemic proportions plaguing our understanding of inflammation’s role in cancer is blanket over-reliance on pre-clinical mouse models which are increasingly recognized to poorly recapitulate human physiology (, ). Too often, such over-reliance dictates what to examine how and when. For example, mouse models did not predict pituitary gland inflammation (hypophysitis) and colitis as common, severe side effects of , an anti- mAb (monoclonal antibody) approved for use in human metastatic melanoma patients ( , 12) nor did they predict mAbs targeting and would be far more effective compared to those targeting CTLA-4.
II. Inflammation Could Either Help Or Hinder Cancer Growth
Disagreement about the role of tumor-infiltrating immunocytes is long-standing, starting from the very genesis of the field of modern immunology. While Rudolph Virchow saw ‘white’ cell, i.e., leukocyte, infiltrates in solid tumors and in 1863 ascribed to them a cancer-promoting role (), Paul Ehrlich in 1909 proposed the human immune system eliminated nascent tumors (13). However, such opposing views can be reconciled by considering inflammation’s outcome, tumor-promoting or tumor-inhibiting/eradicating, to be inherently context-based. Doing so shifts the spotlight away from outcome to process.
Specifically, dysregulated (unresolved and/or inappropriate) inflammation as tumor-promoting/enabling and regulated inflammation as tumor-inhibiting. In 1972 Alexander Haddow speculated ‘tumor production is a possible overhealing‘ (14). In 1986 Harold F. Dvorak observed inflammation and cancer share some basic developmental features such as angiogenesis and leukocyte infiltration, and suggested tumors were ‘wounds that did not heal‘ (15). Enabling/promoting implies chronic tumor site activation of immunocytes (granulocytes, monocytes, macrophages, mast cells, even eventually lymphocytes) and also fibroblasts () that over time get hopelessly compromised and locked into an unproductive tissue repair/wound healing process that ends up promoting tumor growth (see below from ). Predictably differentiating different types of inflammation locally as well as systemically is very much work in progress.
III. Epidemiological Data Suggesting Dysregulated Inflammation Could Increase Cancer Risk
Albeit indirect, some epidemiological studies estimate infection-driven cancer risk to be considerable.
- Some infections can directly drive the genetic transformation process necessary for cancer. For example, EBV, HPV and HTLV-1 can directly induce cell transformation.
- Other infections may lock in an unproductive chronic inflammation process that enables cancer in those predisposed to it. For example, hepatitis viruses drive chronic inflammation in infected tissues. Reasons for such predisposition could be genetic as well as environmental, with diet and lifestyle being the main drivers of the latter.
- Estimates suggest 15 ( ) to ~18% ( ) of global cancer are infection-related with agents ranging from Helicobater pylori, HPV (human papilloma virus), hepatitis B and C viruses, EBV (Epstein-Barr virus), HIV and herpes, schistosomes, HTLV, and liver flukes. Tumor-promoting inflammation is suspected to be involved in all of them.
- Success of prophylactic vaccines in preventing cancers caused by viral infections has led to the estimate that 10 to 20% of all human tumors could be outcomes of such infections ( , ).
- 25% of all human cancers are estimated to result from chronic inflammation ( ).
IBDs () such as UC and Crohn’s have 10-fold greater colorectal cancer risk ( , ).
Abundant infiltration of renal cell carcinoma by CD4+ and CD8+ T cells with specific features is associated with worse prognosis (, 25, 26).
Age, ethnicity, family history being the major risk factors for prostate cancer would seem to preclude a role for chronic inflammation except its rate rises within one generation of migrating to the US or Western Europe among low-risk Chinese and Japanese men (). Diet and lifestyle would thus be the prime environmental factors with chronic inflammation linking them to prostate cancer, except the particulars of such inflammation are yet unresolved. This may be why epidemiological data on link between chronic inflammation and prostate cancer is a mixed bag, several supporting (28, 29, 30, 31, 32, , , ), some not (36, , 38, , ), with strongest supportive data from studies with larger number of subjects and with confirmed diagnosis of .
Such contradictions emphasize the difficulty inherent to human studies, especially so for solid tumors. Reconstructing an entire process with recourse only to snapshots, be they biopsies or images, can only ever be fraught with uncertainty.
- Different studies used different size biopsies and may have taken them at different stages of the cancer process.
- Different studies used different qualitative approaches to categorize inflammation.
IV. Spontaneous Regressions, William Coley and Coley’s Toxins: Mimicking Acute Infections Could Eradicate Tumors
His observation of several cases of spontaneous tumor regressions in the context of acute infections, specifically infections that induced high fevers, droveto a life-long endeavor of trying to eliminate tumors using infection-mimics in the form of his artisanal ( ). Though Coley’s ideas fell into disfavor and his legacy was ignored through much of the 20th century, the explication of the starting in the 1960s and of the starting in the 1990s reversed that trend with modern cancer immunotherapy a direct inheritor and beneficiary of his ideas.
V. Epidemiological Data That Certain Types Of Inflammation Could Reduce Cancer Risk
Ectopic lymph node-like structures in solid tissues are considered emblematic of chronic inflammation. However, their presence in lung and colorectal cancers is associated with improved prognosis (, , ). As well, such studies show up the limitation of terminology. Clearly even chronic inflammation isn’t inherently tumor-enabling. Process, not outcome and more than one type of chronic inflammation.
- Increased intra-tumoral T cells especially CTL ( ) ( ) are a good prognostic for colon cancer ( , 47).
- Several studies have now found temporally increasing numbers of TIL ( ) in TNBC ( ) correspond to regression-free survival ( , , , , ).
- Patients with colon ( ) and ovarian (54) tumors heavily infiltrated with CTL and NK cells have better prognosis compared to those lacking them.
VI. Epidemiological Data That Reducing Inflammation Reduces Cancer Risk
Daily Aspirin &/Or NSAID Intake Reduces Risk Of Several Cancers
- Several meta-analyses ( , , 57, , , ) suggest daily aspirin but not other NSAID intake consistently shows some protection against prostate cancer incidence.
- of cardiovascular trials found low daily dose (75 to 100mg) of aspirin may reduce cancer incidence and cancer mortality for many cancer types ( , ).
- Meta-analysis of data from 8 RCTs ( ) where patients took daily aspirin to prevent cardiovascular diseases also found lower incidence of cancers, not just colon but also brain, esophageal, lung, pancreatic, prostate and stomach, with the benefit becoming apparent after at least 5 years of daily aspirin while aspirin for >7.5 years reduced 20-year risk of cancer death by 30% for all solid cancers and by 60% for gastrointestinal cancers ( ).
However, drawback of prolonged use of aspirin and NSAIDs is side effects such as stomach and brain bleeds.
Used to treat IBD for >50 years, a meta-analysis of 9 observational studies found drugs such asreduce colitis-associated colorectal cancer risk by 49% (64).
Anti-Diabetic DrugMight Reduce Cancer Risk In The Diabetic
- Meta-analysis ( ) of 11 studies including cohort and case-control studies on 4042 cancer cases and 529 cancer deaths found 31% reduction in cancer incidence and mortality risk among metformin takers.
- Meta-analysis ( ) of 47 independent studies including 65540 cancer cases in diabetic patients found metformin reduced overall cancer incidence and mortality by 31 and 34%, respectively, specifically risk for colorectal cancer.
- Meta-analysis ( ) of 24 independent metformin cohort and case-control studies on 386825 subjects found 30% reduced cancer risk for metformin users.
Metformin might inhibit tumor progression by altering tumor metabolism as well as tumor-associated inflammation ().
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