Exploring the interplay between autoimmunity and cancer to find the target therapeutic hotspots

Figures & data

Figure 1. Autoimmune disorders and its interconnection with carcinogenesis in a cyclic pattern. Mutations in growth regulators, apoptotic proteins lead to both autoimmune disorder and cancer directly or indirectly. Autoimmune disorders caused due to deregulation of cell division proteins lead to inflammation, T-cell activation and B-cell activation which results in intolerance to self-tissues, i.e. immune responses are directed towards self-tissues which ultimately lead to cancer.

Figure 2. Stimulation of various membrane receptors by TNF, EGF, IGF leads to phosphorylation of protein kinase C which mediates the signal to the interior of the cell and activates MAPK and PI3-K dependent pathways. These pathways, in turn, regulate various cellular processes like cellular differentiation, cell division and apoptosis. Apoptosis is induced synergistically via both p53 dependent and caspase-dependent mechanisms. Deregulation in any signalling molecule or a mutation in the gene encoding these molecules of MAPK and PI3K pathways and apoptosis signalling leads to cellular transformation.

Table 1. Putative hotspots for therapeutically targeting autoimmune diseases and cancer.

Target site	Effect on pathogenesis of autoimmunity and cancer	Types of cancer involved
P53	Mutant P53 alters apoptosis, cell cycle, oncogenesis and promotes inflammation	Varieties of Cancer
AKT	Mutant AKT triggers onset of autoimmunity and cancer by abnormal activation differentiation of T-cell and B-cell, induction of cell proliferation, angiogenesis.	Head/Neck squamous cell, Pancreatic, Ovarian, Breast, Thyroid
P13K	Mutant P13K may lead to systemic autoimmunity and cancer by inducing unregulated cell proliferation which triggers inflammation and malignant transformation.	Breast, Endometrial, Hepatocellular, Colon, Prostrate, Gastric, Glioblastoma, Head/Neck squamous cell.
mTOR	Mutant mTOR alters T-cells differentiation, metabolism and has a role in malignant cell survival.	Pancreatic, Colon, Breast, Prostrate.

Table 2. The association of different autoimmune diseases with the symptoms of cancer and the reason the development of malignancy.

Autoimmune disease	Associated cancer	Reason for cancer conditions	References
Rheumatic arthritis	Lymphoproliferative and hematologic malignancies	It may be due to the generation of autoantibodies against self and non-self-antigens, paraneoplastic syndromes or by chemotherapy.	[60]
Polymyositis and dermatomyositis	Risk of cancer of the ovary, non-Hodgkin lymphoma and lung and bladder cancers	The cause of polymyositis is unclear. Autoimmune factors and viruses are the possible reason.	[61,62]
Sjögren’s syndrome	Non-Hodgkin's lymphoma (NHL)	Uncontrolled expansion of B-lymphocytes is a result of various genetic alterations, typically translocations involving immunoglobulin gene loci and proto-oncogenes o	[63]
Systemic lupus erythematosus (SLE)	Non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, as well as solid tumours, as lung, cervical and breast cancer	The frequent presence of NHL in SLE can be due to the chronic, persistent antigen-stimulus, chronic inflammation, uncontrolled B cell proliferation, defected apoptosis, and the increased risk of oncogene translocation.	[2]
Crohn’s disease and ulcerative colitis (IBD)	Exhibited associations with gut malignancies	Multifaceted immune dysregulation. IBD-like diseases can develop due to abnormal Tregs and impaired immune tolerance	[64]
Multiple sclerosis (MS)	Increased risk of developing cancer, particularly breast cancer	T lymphocytes migrate from the periphery into the CNS and adhesion molecules cross the blood–brain barrier and produce an inflammatory response	[65]
Pulmonary fibrosis, including systemic sclerosis	An increased risk of lung cancer in disorders associated with	Recurrent injury and inflammation result in genetic alterations that predispose to lung cancer	[66]
Celiac disease	Intestinal lymphoma and other forms of cancer, especially adenocarcinoma of the small intestine	Immune intolerance for naturally ingested wheat protein, gluten and antibodies for tissue transglutaminases lead to an expansion of enteropathy and associated symptoms	[67]
or Lambert–Eaton myasthenic syndrome	In small cell carcinomas of the lung	Autoantibodies against voltage-gated calcium channels leading to paucity of acetylcholine release at presynaptic membranes	[68]

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