1 Background: current cancer theories and questions
2 Deduction of a new cancer mechanism
2.1 Wounds as risk factors in cancer
Cancer | % of all sites [107] | Wound related |
---|---|---|
Prostate cancer (M) | 25% | |
Breast cancer (F) | 27% | |
Lung and bronchus | 14.5% | |
Colon and rectum | 10% | |
Urinary bladder (M) | 7% | |
Uterine (F) | 6% | |
Skin cancer | 4.5% | |
Non-Hodgkin lymphoma | 4.5% | |
Kidney and renal pelvis | 4% | |
Thyroid (F) | 4% | |
Leukemia (M) | 3% | |
Oral cavity and pharynx (M) | 3% | Gingivitis, lichen planus [125] |
Ovary (F) | 3% | |
Pancreas | 3% | Chronic pancreatitis, hereditary pancreatitis [125] |
Brain and nervous system | 1.5% | |
Liver cancer | 1.5% | |
Gall bladder cancer | 0.7% | Chronic cholecystitis [125] |
Gastric cancer | 1.4% | |
Esophageal cancer | 1.1% | Reflux oesophagitis, Barrett’s esophagus [125] |
Hodgkin lymphoma | 0.6% |
2.2 Oncogenes in wound healing
Genes | Genes in cancer | Gene functions in wound healing process |
---|---|---|
Akt1 | Breast [152] | Acute skin repair was characterized by an increase of Akt1 phosphorylation in wound margin keratinocytes [153] |
Bcl-2 | Breast cancer [154] | |
BRCA2 | Breast, ovary [157] | |
β-catenin | Colon [160] | Inhibited keratinocyte migration and activated fibroblast proliferation. The size of the wounds in the mice correlated with the protein level of ß-catenin [161] |
EGFR | Lung, colon, glioblastoma, pancreas [162] | Regulated multiple facets of cutaneous wound healing, including inflammation, wound contraction, proliferation, migration, and angiogenesis [163] |
Ets-1 | Ovarian [164] | Ets-1 accumulated in migrating cells at the wound edge and returned to basal level when reendothelialization was accomplished [165] |
c-fos | Prostate [166] | |
FGFR3 | Myeloma [162] | FGFRs played crucial roles in the repair of skeletal tissues [169] |
GROα | Breast cancer [170] | At day 1 after injury, growth-related oncogene α were maximally expressed in the superficial wound bed and were spatially and temporally associated with neutrophil infiltration. It correlated with keratinocyte migration and subsequently subsided after wound closure at day 4 [171] |
Her-2 | Breast, lung, ovarian [162] | Depletion of functional Her-2 attenuated the healing of scratch wounds [172] |
c-Jun | Prostate [173] | Expressed in epithelia in early stages165; Increased in apoptotic cells of wound healing [174] |
c-met | Gastric, lung [162] | c-Met signaling not only controlled cell growth and migration during embryogenesis but was also essential for the generation of the hyperproliferative epithelium in skin wounds, and thus for a fundamental regenerative process in the adult [175] |
c-myc | Lymphoma, Leukemia [162] | |
MMP-7 | Colon [160] | Involved in intestinal re-epithelialization in vivo and upregulated by cytokines relevant in wound repair [178] |
p53 | Cervical, multiple [162] | A tumor suppressor gene. It was decreased in the first 2 days after wound, increased in 3–5 days and returned to normal after 9 days on the swine skin wound healing process [179] |
p63 | Invasion and metastasis [180] | A tumor suppressor gene. It was silent in the early days, but activated in later time on wound healing process [181] |
PDGFR | Glioma, gastrointestinal [162] | Platelet-derived growth factor (PDGF) isoforms stimulated cell proliferation, migration and survival. The hyperactive PDGFR-ß mainly affected the early proliferative response after injury [182] |
PI3K | Breast [183] | The impairment of PI3K/AKT pathway is a key factor contributing to the delayed epithelial wound healing in diabetic corneas [184] |
PTEN | Gliomas [162] | A tumor suppressor gene. Injury to the cornea downregulated PTEN expression and contributed significantly to enhance cell migration in wound healing [185] |
Raf-1 | Ovarian [186] | Raf-1 is required for normal wound healing in vivo and for the migration of keratinocytes and fibroblasts in vitro [187] |
Ras | Pancreatic, thyroid, colon [162] | Activation of Ras led to wound epithelialization [188] |
Sox-2 | lung and esophageal [189] | Skin-derived precursors derived from Sox2(+) follicle-associated dermal precursors and displayed functional properties predicted of a dermal stem cell, contributing to dermal maintenance, wound-healing, and hair follicle morphogenesis [190] |
Src | Breast [191] | Src was activated in cells along the wound edge and blocking this activation with the Src kinase inhibitor, PP1, inhibited wound closure by 85% [192] |
VEGF | Tumor angiogenesis [162] | Contributed to neovascularization during wound healing [193] |
2.3 Cancer appearances in multicellular organisms
Species | Lifespan | Wound healing | Cancer |
---|---|---|---|
Plant, e.g., pine | ∼1,500 Years [194] | Response to stop further damage only. No recruited cells and no original wound recovery [195] | Noa
|
Porifera, e.g., sponge | 4 Years [196] | Mesohyl cells infiltrated and proliferated [197]. No cell recruitment found | Hard to findb
|
Cnidaria, e.g., jellyfish | 1 Year [198] | Cell migration and differentiation to heal small wounds. No cell proliferation [199] | Hard to find |
Hydrozoa, e.g., hydra | ∼Immortal [200] | Cell proliferation, differentiation and regeneration [201] | Hard to find |
Annelid, e.g., earthworm | 8 Years [202] | Completele regeneration from amputation by blastema [203] | Yes [204] but scarce |
Arthropod, insect, e.g., Drosophila | 12 Days [205] | ||
Chordate, actinopterygius, e.g., Zebrafish | ∼66 Months [210] | Yes [215] | |
Amphibia, e.g., newt | 30 Years [216] | Yes but difficult [219] | |
Aves, e.g., chicken | 7 Years [220] | ||
Mammal, e.g., mouse and human | Yes, many |
2.4 Cancer mechanism on mammals
Logic | Published studies on mammal cells | Indication |
---|---|---|
L1 | Human and mouse wound healing involved reepithelialization, epidermal differentiation, cell migration, proliferation, inflammatory response as well as dermal closure, matrix distribution, and skin remodeling [223] | Wound healing in mammal is a complicated procedure |
Healing of cutaneous wounds required a complex integrated network of repair mechanisms, including the action of newly recruited leukocytes [171] | ||
L2 | Many molecules were highly expressed or secreted, and involved in the process of wound and wound healing, including Bcl-2, Bcl-XL, fas-fas ligand, TNF-TNF receptor, p53, caspases, etc. [229] | Many growth factors, cytokines, and other proteins are highly expressed or secreted during the occurrence of the wound and wound healing. Those molecules also appear in cancer |
T lymphocytes infiltrated wounds and tumors, synthesized and exported two well-characterized growth factors, heparin-binding epidermal growth factor-like growth factor (HB-EGF) and basic fibroblast growth factor (bFGF), mediating fibroblasts and smooth muscle cells formations in the angiogenesis associated with wound healing and tumor growth [230] | ||
Cytokines produced by or carried within platelets could be released at sites of vascular injury and participate in wound healing [231] | ||
Human γδ-T cells secreted connective tissue growth factors during wound healing [232] | ||
L3 | Wound fluids, especially on early time (day 1) promoted tumor growth on mice [68] | Wound activated oncogenes and induced cancerization |
Substance–P, SCF, IL–1 and VEGF were markedly induced after alkali burn at mouse eye as well as peripheral blood. Substance–p was the early cytokine induced by alkali burn wound and stimulated cell proliferation and mobilization of mesenchymal stem cells [233] | ||
c-Fos- and c-Jun-immunoreactive cells were detected in the epithelial cells and keratocytes around the experimental physical and chemical cornea injuries on rats [234] | ||
L4 | In a murine experimental glioblastoma model, endogenous neural precursors migrated from the subventricular zone toward the tumor, surrounded it, and induced glioblastoma cell apoptosis [235] | Tumor cells recruit stem cells to the tumor sites. Cytokines migrate and differentiate cells in the wound healing |
During wound healing, quiescent corneal keratocytes surrounding the injured region differentiated into fibroblast or myofibroblast phenotypes that mediate cell migration, wound contraction, and matrix remodeling. In a 3D culture model of the corneal stroma, TGF-β induced the corneal keratocytes to differentiate into myofibroblasts, and PDGF stimulated significant keratocyte migration [236] | ||
L5 | Fifteen min after the rat cornea epithelial ablation, weak signals for c-fos and c-jun mRNAs were detected in the corneal epithelium surrounding the wound. These signals reached a peak 30–60 min after ablation, but were no longer evident at 120 min [167] | Oncogenes express in the early stage of a wound. Tumor suppressing genes express in the late stage of a wound. After the wound healing, those genes are back to homeostasis. Cancer secretes molecules with the power to heal wounds in the body |
p53 expression was decreased to negative in the first 2 days after wound, increased in 3–5 days and returned to normal after 9 days on the swine skin wound healing process. In contrast, the oncogene PDGFR expression was negative before wound and increased 6 h after wound, peak at 1–3 days and returned to normal 9 days after wound [179] | ||
In the first day after the human skin wound, there was a dramatic downregulation of p63 expression in wound area. Five days after the injury, induction of p63 in the basal keratinocytes could be detected, followed by a gradual increase of its expression in subsequent days. Several days after complete wound closure, p63 was still strongly expressed not only in the basal keratinocytes but also in the entire spinous layer, whereas the Ki67 expression was restricted to single cells in the basal layer [181] | ||
The plasma from tumor-bearing mice healed the wound faster than the plasma from normal mice [45] | ||
L6 | Chronic inflammation and persistent wound healing reactions in large and small bile ducts often lead to liver cancer [237] | Chronic wounds make oncogenes highly expressed. Oncogenes transform some cells into cancer cells. Cancer cells secrete molecules that help to heal wounds |
The level of both c-fos and c-Ha-ras mRNAs were heavily induced in the basal layer of epidermis in chronic wounds when compared to normal skin and acute wounds [238] | ||
c-Ki-ras oncogene was frequently activated in mucous cell hyperplasias of pancreas suffering from chronic inflammation [239] | ||
The activated Ras oncogene transformed various mammalian cells and had been implicated in development of a high population of malignant human tumors [240] | ||
Platelet-rich plasma obtained from healthy (PRP) or tumor-bearing (TPRP) mice was applied to dorsal, full-thickness wounds on diabetic mice. TPRP-treated wounds reached 90% wound closure 5.6–9.5 days earlier than PRP-treated and nontreated wounds, respectively [45] | ||
L7 | After corneal injury, the neurotrophic factor PEDF was increased in the media at a relative late wound stage (48 h) [241] | Some molecules appeared in the wound healing play a potential role in promoting differentiation of cancer cells |
PEDF blocked angiogenesis and induced differentiation in prostate cancer [242] | ||
FGF-2 increased after wound closure and inhibited the early increased TGF-β. TGF-β increased the stromal cell migration for wound healing [243] | ||
Intracellular FGF-2 significantly inhibited the migratory potential of T-47D breast cancer cells and promoted those cell differentiations [244] | ||
L8 | PEDF induced endothelial HUVEC apoptosis through the sequential induction of PPARgamma and p53 overexpression [245] | Some wound healing molecules induced apoptosis of angiogenesis and cancer cells |
Overexpression of FGF-2 downregulated the oncogene Bcl-2 and promoted apoptosis in MCF-7 human breast cancer cells [246] | ||
L9 | Necrotic cells were characterized by the loss of membrane integrity, organelle swelling, lysosomal leakage, and inducing a significant inflammatory response [229] | Necrosis occurs during the cancer mass expansion due to the nutrient deficiency and hypoxia |
Cancer cell expansion, remodeling and regression induced apoptosis and necrosis due to the nutrient deficiency and hypoxia [247] | ||
Hypoxia induced both apoptosis and necrosis through the pathways of HIF-1 and NIP3 [248] | ||
L10 | Spontaneous regression of cancer was reported in virtually all types of human cancer [249] | The existence of spontaneous regression of cancer indicates that cancer, even an advanced one can be a reversible process |
Spontaneous regression was reported on multiple sites of melanoma [250] | ||
A complete clinical spontaneous regression was reported on a lung cancer with metastases of abdominal wall, liver, and lung [251] | ||
Approximately one half of all cancer patients experienced a complex metabolic status involving progressive exhaustion of adipose and skeletal muscle tissue–cachexia [252] |