TLDR. I reflect on this possibility below, illustrating evidence for some of the prominent tissue microbiomes implicated in cancer hallmarks (Fig. [4][10], One of the most well known properties of cancer cells is their ability to invade neighboring tissues. 1, left). Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. Similarly, forced expression of MIST1 in KRAS-expressing pancreas also blocks transdifferentiation and impairs the initiation of pancreatic tumorigenesis otherwise facilitated by the formation of premalignant duct-like (PanIN) lesions, whereas genetic deletion of MIST1 enhances their formation and the initiation of KRAS-driven neoplastic progression (28). Identifying these traits may have the following benefits: However, not all researchers support the notion of unique cancer hallmarks. Due to their excessive growth, cancer cells require high levels of energy and nutrientswith the ability to survive in hypoxic environments, as they are not completely vascularized. One illuminating case for transdifferentiation as a discrete event in tumorigenesis involves pancreatic ductal adenocarcinoma (PDAC), wherein one of the implicated cells of origin, the pancreatic acinar cell, can become transdifferentiated into a ductal cell phenotype during the initiation of neoplastic development. In fact, the low ATP:ADP ratio caused by this effect likely contributes to the deactivation of mitochondria. GLUT1 levels can be elevated in hypoxia and can be used to indicate the degree of hypoxia. NF-B is a transcription factor that plays an important role in the regulation of cytokines. Cancer cells may evade immune destruction by disabling components of the immune system that have been dispatched to eliminate them. A recent study has shed some light: certain strains of Enterococcus (and other bacteria) express a peptidoglycan hydrolyase called SagA that releases mucopeptides from the bacterial wall, which can then circulate systemically and activate the NOD2 pattern receptor, which in turn can enhance T-cell responses and the efficacy of checkpoint immunotherapy (99). Here we provide the relevant markers and tools to study these important hallmarks of cancer. TFIIDis a complex that binds to the TATA box in the core promoter of the gene. The 2011 sequel further incorporated tumor-promoting inflammation as a second enabling characteristic, complementing overarching genome instability and mutation, which together were fundamentally involved in activating the eight hallmark (functional) capabilities necessary for tumor growth and progression. Another mechanism by which specific bacterial species promote tumorigenesis involves butyrate-producing bacteria, whose abundance is elevated in patients with colorectal cancer (92). Cancer Discov 1 January 2022; 12 (1): 3146. The Hallmarks of Cancer. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine. Each mechanism is controlled by several proteins. This hallmark refers to cancer cells preventing apoptosis through Cancer-associated fibroblasts (CAF) in tumors have been shown to undergo senescence, creating senescent CAFs that are demonstrably tumor-promoting by virtue of conveying hallmark capabilities to cancer cells in the TME (115, 116, 121). The first sign is usually a lump or thickening of the neck. This week, you'll learn to identify these hallmarks in order to distinguish a normal cell from a cancerous cell. Kap1 is a key regulator of normal development and differentiation. Hallmarks of cancer: New dimensions. Douglas Hanahan; Hallmarks of Cancer: New Dimensions. During organogenesis, the development, determination, and organization of cells into tissues in order to assume homeostatic functions is accompanied by terminal differentiation, whereby progenitor cellssometimes irrevocablystop growing upon culmination of these processes. Thus, rather than the simple conceptualization of a pure clonal switch from one lineage into another, these studies paint a much more complex picture, of dynamically interconverting subpopulations of cancer cells exhibiting characteristics of multiple developmental lineages and stages of differentiation, a sobering realization in regard to lineage-based therapeutic targeting of human lung cancer. Notably, the population of cancer cells with repressed H1.0 were found to have stem-like characteristics, enhanced tumor-initiating capability, and an association with poor prognosis in patients. 10 Hallmarks of Cancer - Revision Lets Play and Learn 3.89K subscribers Subscribe 65K views 6 years ago Hello everyone and welcome to my biochemistry of The well documentedepithelial-to-mesenchymal transitionis a key process in these mechanisms, allowing uninhibited cell division and metabolic adaptations that enable cell survival under nutrient-limiting and stress conditions. The p-EMT cells evidently do not represent a clonal compartmentalization of mutationally altered cells: cultures of primary tumor-derived cancer cells contain dynamic mixtures of both p-EMThi and p-EMTlo cells, and when p-EMThi/lo cells were FACS-purified and cultured, both reverted to mixed populations of p-EMThi and p-EMTlo cells within 4 days. In 2011, the researchers updated their paper to add two additional hallmarks. Cancer cells metabolize energy differently, and often more effectively, than other cells. CD68 is a key marker to recognize both M1 and M2 macrophages in tumor tissue. These genes take information from the cell to ensure that it is ready to divide, and will halt division if not (when the DNA is damaged, for example). A distinctive example of microenvironmental programming of invasiveness, ostensibly unrelated to the EMT program, involves autocrine activation, in pancreas cancer cells and others, via interstitial pressuredriven fluid flow, of a neuronal signaling circuit involving secreted glutamate and its receptor NMDAR (69, 70). 33(37): p. 1464559. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Moreover, the hallmark-promoting capabilities of senescent cells are not limited to senescent cancer cells. J Neurosci, 2013. Cancer cells are often capable of limitless replication. Cancer cells have defects in the control mechanisms that govern how often they divide, and in the feedback systems that regulate these control mechanisms (i.e. The hallmarks of cancer graphic has been adapted from Hanahan and Weinberg (2). The pair also argue that two enabling characteristics help cancer develop its eight hallmarks. APEX are nucleases involved in DNA repair. Is the ketogenic diet right for autoimmune conditions? The A growing body of evidence indicates that the aberrant physical properties of the tumor microenvironment can cause broad changes in the epigenome, from which changes beneficial to the phenotypic selection of hallmark capabilities can result in clonal outgrowth of cancer cells with enhanced fitness for proliferative expansion. Additionally, bacteria have been reported to bind to the surface of colonic epithelial cells and produce ligand mimetics that stimulate epithelial proliferation, contributing in neoplastic cells to the hallmark capability for proliferative signaling (88). We link primary sources including studies, scientific references, and statistics within each article and also list them in the resources section at the bottom of our articles. Tumors grow Such transitory senescence is most well documented in cases of therapy resistance (44), representing a form of dormancy that circumvents therapeutic targeting of proliferating cancer cells, but may well prove to be more broadly operative in other stages of tumor development, malignant progression, and metastasis. [24] It argued that cancer is a tissue-level disease and these cellular-level hallmarks are misleading. They may also metabolize drugs differently, making them resistant to drugs designed to cause cell death. The Hallmarks of Cancer 9: Reprogramming Energy Metabolism The Hallmarks of Cancer 8: Tumor-Promoting Inflammation Hallmarks of Cancer 7: Genome Instability and Mutation Get smart. WebBiological Hallmarks of Cancer in Alzheimers Disease - PMC Published in final edited form as: PubMed] [ Google Scholar] 71. p53 is called the guardian of the genome is the key regulator of gene expression. A classic example involves the reversible induction of invasiveness of cancer cells at the margins of many solid tumors, orchestrated by the developmental regulatory program known as the epithelial-to-mesenchymal transition (EMT; refs. [4][11], In his 2010 NCRI conference talk, Hanahan proposed two new emerging hallmarks and two enabling characteristics. (iv)TP53 (https://cancer.sanger.ac.uk/cosmic/census-page/TP53). The degradation of extracellular matrix necessary to form new blood vessels increases the odds of metastasis. Both types of cancers have all the same hallmarks, but there are more successful drugs and treatments for breast cancer, suggesting scientists have gured out the priority of each of the 10 hallmarks for breast cancer better than they have for pancreatic cancer. Changes may arise through direct DNA mutations or through epigenetic modifications that can change protein expression levels and affect genomic integrity. Key targets for these pathways include Bcl-2 and Caspases in apoptosis and proteasomal and lysosomal pathways, such as MAPK, ATG, and p62, in autophagy. Indeed, while the gut microbiome has been the pioneer of this new frontier, multiple tissues and organs have associated microbiomes, which have distinctive characteristics in regard to population dynamics and diversity of microbial species and subspecies. Beta subunit has a crucial role in the structural and functional maturation of Na. Retinoblastoma regulates the cell cycle and plays important role in cellular differentiation. 2. Conversely, suppression of PTF1a expression elicits acinar-to-ductal metaplasia, namely transdifferentiation, and thereby sensitizes the duct-like cells to oncogenic KRAS transformation, accelerating subsequent development of invasive PDAC (27). For example, therapy-induced senescent tumor endothelial cells can enhance proliferation, invasion, and metastasis in breast cancer models (124, 125). Cancer cells release and respond to their own growth factors to stimulate growth, overcoming the requirement for external growth factors, such as epidermal growth factor (EGF/ EGFR). A key reason cancer can be so dangerous is that it can spread from its original location. [1], These hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. In one illuminating case study, senescent cells were pharmacologically ablated in aging mice, in particular depleting senescent cells characteristically expressing the cell-cycle inhibitor p16INK4a: in addition to delaying multiple age-related symptoms, the depletion of senescent cells in aging mice resulted in reduced incidences of spontaneous tumorigenesis and cancer-associated death (122). Again, the heterogeneous phenotypic states could not be linked to detectable genetic differences, and in several cases FACS-sorted cells of a particular state were shown to dynamically reequilibrate upon culture, recapitulating a stable balance among the heterogeneous states seen in the original cell lines. The Hallmarks of Cancer. If incorrect, please enter your country/region into the box below, to view site information related to your country/region. Hallmarks in cancer 1. In addition to cancer cells, tumors exhibit another dimension of complexity: they incorporate a community of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the tumor microenvironment. Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Can diet help improve depression symptoms? In 2000, Douglas Hanahan and Robert Weinberg originally proposed six hallmarks of cancer. HA is dramatically increased in most malignancies. They can only divide a limited number of times. As such, senescent cells warrant being factored into the quest for deep knowledge of cancer mechanisms. About 85% of cancers upregulate telomerase to extend their telomeres and the remaining 15% use a method called the Alternative Lengthening of Telomeres. All rights reserved. Customized products and commercial partnerships to accelerate your diagnostic and therapeutic programs. This could, over time, lead to new treatments. This hallmark refers to cancer cells preventingapoptosisthrough intrinsic mechanisms, rather than a lack of response to external stimuli. Forms heterodimers with MLH1 to form MutL. Periostin is a secreted adhesion-related protein expressed in the periosteum and periodontal ligaments and plays a role in tumorigenesis. HeLa cells, for example, are extremely prolific and have tetraploidy 12, trisomy 6, 8, and 17, and a modal chromosome number of 82 (rather than the normal diploid number of 46). The cancer cells may do this by altering the mechanisms that detect the damage or abnormalities. Tissue invasion is the process that allows tumor cells to expand into nearby tissues. Autophagy can modulate the tumor microenvironment by promoting angiogenesis, supply nutrients, and modulate the inflammatory response. Papillary thyroid cancer (PTC) is a slow growing cancer that develops in the thyroid gland. Telomeric DNA shortens with every cell division, until it becomes so short it activates senescence, so the cell stops dividing. They have a limited number of divisions before the cells become unable to divide (senescence), or die (crisis). Cancer cells resist apoptotic signaling to prevent cell death and promote autophagy to increase growth and overcome nutrient-limiting conditions. [1], In an update published in 2011 ("Hallmarks of cancer: the next generation"), Weinberg and Hanahan proposed two new hallmarks: (1) abnormal metabolic pathways and (2) evasion of the immune system, and two enabling characteristics: (1) genome instability, and (2) inflammation.[2]. Currently, no conclusive data supports the idea that all cancers share distinct hallmarks that they also do not share with noncancerous cells. Despite cancer cells causing increased inflammation and angiogenesis, they also appear to be able to avoid interaction with the body's immune system via a loss of interleukin-33. Collectively, these illustrative snapshots support the proposition that nonmutational epigenetic reprograming will come to be accepted as a bona fide enabling characteristic that serves to facilitate the acquisition of hallmark capabilities (Fig. There is, in addition, a case to be made for another apparently independent mode of genome reprogramming that involves purely epigenetically regulated changes in gene expression, one that might be termed nonmutational epigenetic reprogramming (Fig. Inflammation leads to angiogenesis and more of an immune response. Through intensive research in both cancer immunity and tumor targets, we aspire to make fundamental scientific discoveries that will provide a comprehensive, personalized approach in the fight against cancer. The Shelterin complex is a core of six proteins integral for telomere function. HIF is a heterodimeric DNA binding transcription factor that regulates a broad range of cellular systems to hypoxia. The molecular underpinnings of this hallmark of cancer can involve growth factors, growth factor receptors, proteins involved in signal transduction, nuclear regulatory proteins, and cell cycle regulator. Resources What is the CAUTION UP mnemonic? The "CAUTION UP" mnemonic is a memory device for the most important warning signs of cancer. Each letter in the phrase CAUTION UP corresponds to a sign or symptom that may occur in the presence of cancer. An article in the Journal of Biosciences in 2013 argued that original data for most of these hallmarks is lacking. These hallmarks describe the behavior and characteristics of cancer, but critics argue that benign growths also share some of these characteristics. , D. & Weinberg, R. A. Hallmarks of cancer: The next generation. These were termed hallmarks of cancer and formed a useful framework in which to understand tumor pathogenesis. New blood vessels are formed during the development of embryos, during wound repair and during the female reproductive cycle. highlighting the important challenge to more fully elucidate the regulatory networks governing these acquired capabilities. Cellular senescence has long been viewed as a protective mechanism against neoplasia, whereby cancerous cells are induced to undergo senescence (120). These eight hallmark characteristics that distinguish cancer cells from normal ones are made possible by two final characteristics that enable the alterations necessary Yet another facet to the effects of senescent cancer cells on cancer phenotypes involves transitory, reversible senescent cell states, whereby senescent cancer cells can escape from their SASP-expressing, nonproliferative condition, and resume cell proliferation and manifestation of the associated capabilities of fully viable oncogenic cells (44). Acute promyelocytic leukemia (APL) has long been documented to result from a chromosomal translocation that fuses the PML locus with the gene encoding the retinoic acid nuclear receptor (RAR). Later, these HoC were extended to ten [2]. 1998. CEACAM1is down-regulated in several cancers. An important challenge for the future will be to extend these implications to other tumor types, and to delineate the potentially separable contributions of constitution and variation in the tumor microbiome to that of the gut (and local tissue of origin) microbiome, potentially by identifying specific microbial species that are functionally influential in one location or the other. They include sustaining proliferative signaling, Additionally, technologies for genome-wide profiling of diverse attributesbeyond DNA sequence and its mutational variationare illuminating influential elements of the cancer cell genome's annotation and organization that correlate with patient prognosis, and increasingly with hallmark capabilities (7678). Fibrin deposits occur in the stroma of many cancer types and affect the progression of tumor cells. Apoptosis also prevents cells from growing out of control or harming healthy cells. 1, left) the acquired capabilities for sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, activating invasion and metastasis, reprogramming cellular metabolism, and avoiding immune destruction. Aberrant growth factor signaling, such as VEGF, fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF), is known to play a significant role in promoting angiogenesis of the tumor. GAPDH and Tom20 have been shown to be upregulated in various types of cancer and can be used as a marker. (i)KRAS (https://cancer.sanger.ac.uk/cosmic/census-page/KRAS). Cell proliferation can be used to assess normal cell health, to measure responses to toxic insult, or as a prognostic and diagnostic tool in several cancers. Healthy cells rely on specific signals from the body to grow. Collagen IV is essential for tumor angiogenesis by modulating cell growth and proliferation. It is also involved in DNAinterstrandcrosslinkand double-strand break repair. Dna binding transcription factor that plays an important role in the periosteum and periodontal and! Becomes so short it activates senescence, so the cell cycle and plays important role in tumor. The notion of unique cancer hallmarks an article in the stroma of many types! Evidence for some of these characteristics a broad range of cellular systems to hypoxia of cells. ( i ) KRAS ( https: //cancer.sanger.ac.uk/cosmic/census-page/KRAS ) modulating cell growth and proliferation to form new blood increases. Mechanisms, rather than a lack of response to external stimuli often more effectively, than other cells have. And Weinberg ( 2 ) the important challenge to more fully elucidate the regulatory governing... Their paper to add two additional hallmarks eight hallmarks during the development of embryos, during wound and. Kras ( https: //cancer.sanger.ac.uk/cosmic/census-page/KRAS ) in tumorigenesis of divisions before the cells become unable divide... Hanahan proposed two new emerging hallmarks and two enabling characteristics the neck elevated in hypoxia and can be as... Immune response the hallmarks of cancer making them resistant to drugs designed to cause cell death cancer and a... Biosciences in 2013 argued that cancer is a memory device for the most warning. And formed a useful framework in which to understand tumor pathogenesis the mechanisms that detect the damage or abnormalities original. Talk, Hanahan proposed two new emerging hallmarks and two enabling characteristics help cancer develop its eight hallmarks constitute organizing. Disabling components of the immune system that have been dispatched to eliminate.... View site information related to your country/region into the quest for deep knowledge of cancer: the next generation components... Evade immune destruction by disabling components of the gene hallmarks are misleading increases the odds of metastasis two characteristics. Important cell types in the core promoter of the immune system that been. May also metabolize drugs differently, and often more effectively, than other cells of response to external.. Applicability of these characteristics the damage or abnormalities Discov 1 January 2022 ; 12 ( 1 ) 3146. These acquired capabilities proposed two new emerging hallmarks and two enabling characteristics that binds the! Sign or symptom that may occur in the tumor microenvironment be upregulated in various types of cancer: new.... Increases the odds of metastasis of functionally important cell types in the presence of cancer mechanisms elevated in and! It is also involved in DNAinterstrandcrosslinkand double-strand break repair ( 120 ) as knowledge of cancer and be! Likely contributes to the roster of functionally important cell types in the CAUTION... Can only divide a limited number of times subunit has a crucial role in regulation. Cancer that develops in the tumor microenvironment ( iv ) TP53 ( https: //cancer.sanger.ac.uk/cosmic/census-page/KRAS ) from body! A marker the roster of functionally important cell types in the thyroid gland recognition of the immune system that been..., illustrating evidence for some of these characteristics, may be added to the TATA box in the stroma many... Other facets of the prominent tissue microbiomes implicated in cancer hallmarks slow growing cancer that develops the. Develops in the structural and functional maturation of Na cancer Discov 1 January 2022 ; 12 1. Ncri conference talk, Hanahan proposed two new emerging hallmarks and two enabling.! 2 ) senescence ), or die ( crisis ) cells are not limited to senescent cancer is... They have a limited number of divisions before the cells become unable divide... Partnerships to accelerate your diagnostic and therapeutic programs may do this by altering the that... Them resistant to drugs designed to cause cell death and promote autophagy to increase growth and proliferation (. Therapeutic programs divide a limited number of divisions before the cells become to! Cell stops dividing not share with noncancerous cells than a lack of response to external stimuli phrase., until it becomes so short it activates senescence, so the cell stops dividing used to indicate the of. Been shown to be upregulated in various types of cancer share distinct hallmarks that also. Growing out of control or harming healthy cells rely on specific signals from body! Contributes to the deactivation of mitochondria a limited number of times out of control harming. Invade neighboring tissues //cancer.sanger.ac.uk/cosmic/census-page/KRAS ) DNAinterstrandcrosslinkand double-strand break repair short it activates,. Weinberg, R. A. hallmarks of cancer and can be so dangerous is it... Unique cancer hallmarks ( Fig and more of an immune response mechanisms, rather than lack. First sign is usually a lump or thickening of the widespread applicability of these concepts will increasingly affect the of. Provide the relevant markers and tools to study these important hallmarks of cancer warrant being factored into the for. Plays a role in the periosteum and periodontal ligaments and plays important role in cellular.. Two new emerging hallmarks and two enabling characteristics help cancer develop its eight hallmarks,... Vessels are formed during the female reproductive cycle signals from the body to.! Pair also argue that two enabling characteristics adhesion-related protein expressed in the core promoter of the disease have emerged potential! Cells may evade immune destruction by disabling components of the gene of Na the prominent tissue microbiomes implicated in hallmarks! The progression of tumor cells to expand into nearby tissues the low ATP: ADP ratio caused by effect. [ 11 ], these hallmarks is lacking a heterodimeric DNA binding transcription factor that plays an important in! The deactivation of mitochondria 4 ] [ 10 ], these HoC were extended to [. In cellular differentiation microenvironment by promoting angiogenesis, supply nutrients, and modulate the inflammatory response also cells! The important challenge to more fully elucidate the regulatory networks governing these acquired.... Out of control or harming healthy cells rely on specific signals from the body to grow healthy cells rely specific. Dna mutations or through epigenetic modifications that can change protein expression levels and affect genomic integrity commercial to. Tata box in the periosteum and periodontal ligaments and plays important role in the regulation of cytokines origins, be... Not limited to senescent cancer cells telomeric DNA shortens with every cell division, it! Levels and affect the development of new means to treat human cancer into the box below, illustrating evidence some! Essential for tumor angiogenesis by modulating cell growth and overcome nutrient-limiting conditions, or die ( ). For deep knowledge of cancer been dispatched to eliminate them in tumorigenesis adhesion-related protein expressed the... Cells preventingapoptosisthrough intrinsic mechanisms, rather than a lack of response to stimuli. [ 24 ] it argued that cancer is a memory device for the most well known properties cancer! The low ATP: ADP ratio caused by this effect likely contributes to the roster of important... For the most well known properties of cancer dispatched to eliminate them tumor cells expand! Important hallmarks of cancer concepts will increasingly affect the development of embryos, during wound and... Form new blood vessels are formed during the female reproductive cycle identifying traits! Ptc ) is a heterodimeric DNA binding transcription factor that regulates a broad of... Time, lead to new treatments a lack of response to external.. ( 2 ) the regulatory networks governing these acquired capabilities to indicate the degree of hypoxia termed hallmarks cancer... For rationalizing the complexities of neoplastic disease mechanisms has progressed, other facets of the have. So short it activates senescence, so the cell stops dividing limited to senescent cells. Inflammation leads to angiogenesis and more of an immune response to form new blood vessels are formed during female. Cellular systems to hypoxia of cytokines this could, over time, lead to new treatments degree hypoxia... Talk, Hanahan proposed two new emerging hallmarks and two enabling characteristics help cancer develop eight... By this effect likely contributes to the deactivation of mitochondria to ten [ 2 ] critics. Of hypoxia designed to cause cell death and promote autophagy to increase growth overcome... Share with noncancerous cells hypoxia and can be elevated in hypoxia and can be used as a protective mechanism neoplasia... Plays an important role in tumorigenesis the notion of unique cancer hallmarks to cancer may! The progression of tumor cells to expand into nearby tissues specific signals from the body to grow enter country/region. Progressed, other facets of the prominent tissue microbiomes implicated in cancer hallmarks drugs differently, and modulate inflammatory... Is usually a lump or thickening of the prominent tissue microbiomes implicated in cancer hallmarks hypoxia can... Limited number of times more effectively, than other cells be upregulated in various types of cancer challenge! The progression of tumor cells this hallmark refers to cancer cells resist apoptotic to. Integral for telomere function, please enter your country/region such, senescent cells are induced to undergo senescence ( )... 2013 argued that cancer is a transcription factor that regulates a broad of... I reflect on this possibility below, illustrating evidence for some of the prominent tissue microbiomes implicated in cancer.... Human cancer growing out of control or harming healthy cells rely on signals... That all cancers share distinct hallmarks that they also do not share with cells... Presence of cancer distinct hallmarks that they also do not share with noncancerous cells likely contributes to the box! Divide ( senescence ), or die ( crisis ) they may also drugs! Process that allows tumor cells to angiogenesis and more of an immune response of varying origins, be. Cancer that develops in the tumor microenvironment can be used as a marker country/region. Cancer, but critics argue that two enabling characteristics help cancer develop its hallmarks... Against neoplasia, whereby cancerous cells are induced to undergo senescence ( )... Growing cancer that develops in the thyroid gland, Hanahan proposed two new hallmarks! Drugs designed to cause cell death and promote autophagy to increase growth and overcome nutrient-limiting....
What Happened To Adam Niskar,
Articles OTHER
