Epistemology of the Origin of Cancer II: Fibroblasts Are the First Cells to Undergo Neoplastic Transformation.

BACKGROUND/AIMS: Many questions in cancer biology remain unanswered. Perhaps the most important issues remaining to be addressed focus on the molecular basis of carcinogenesis. Today's cancer focus lies on genetics and gene expression, which is unlikely to explain the true cause of most cancers or lead to a cure. METHODS: Earlier, we provided a plausible mechanism for this process, specifically, that most cancers develop in response to pathogenic stimuli that induce chronic inflammation, fibrosis, and remodeling of the cellular microenvironment. Collectively, these changes generate a precancerous niche (PCN) in which fibrosis and remodeling are ongoing secondary to persistent inflammation, followed by the deployment of a chronic stress escape strategy (CSES). If the CSES is unsuccessful, the cell undergoes a normal cell to cancer cell transformation (NCCT). RESULTS: Here, we highlight the critical role of fibroblasts as the first cells to undergo neoplastic transformation to a cancerous phenotype which is based on several critical findings. First, persistent disruption of homeostatic crosstalk increases lysyl oxidase activity and lysine oxidation which leads to increased collagen stiffness and decreased elasticity. If unresolved, chronic tissue stress will lead to an escape strategy that involves the recruitment of fibroblasts and fibrocytes from the bone marrow as well as cells undergoing an epithelial-mesenchymal transition (EMT). This yields a heterogeneous pool of cells that express both epithelial and mesenchymal markers and that will ultimately differentiate into cancer-associated fibroblasts (CAFs). Finally, CAFs undergo a mesenchymalepithelial transition (MET) and express epithelial markers that facilitate their integration into the target tissue. CONCLUSION: Here, we review the published findings that led us to this conclusion which is the most plausible answer to this critical question.

Physics Essentials Enable Deeper Understanding in Signaling and Crosstalk of the Carcinogenesis Paradigm "Epistemology of the Origin of Cancer".

Radioactivity and radiation-induced mutations are believed to be primary causal examples of cancer-initiating events (stimulus). The assumption that an increase in cancer risk develops from any amount of radiation gave rise to the linear no-threshold model. This also led to the assumption that cancer is caused by somatic mutations as described by the somatic mutation theory. Against this backdrop, in actuality only ~5%-10% of cancers result from somatic mutations or its various modifications, while ~80% of cancers are still termed as 'sporadic', meaning that their cause is unknown. Therefore, both the linear no-threshold model and the somatic mutation theory have resulted in an incongruity in thinking. Decades of molecular and clinical research since 2012 led to the development of the cancer paradigm, "Epistemology of the origin of cancer", which explains why the majority of cancers originate as a result of a sixstep sequence of events. An understanding of the essentials of physics helps to explain the interconnections between physics and the biology of cancer. This allows for a much-needed reconciliation of past errors and leads to a deeper understanding of carcinogenesis.

Somatic Mutation Theory - Why it's Wrong for Most Cancers.

Hysteron proteron reverses both temporal and logical order and this syllogism occurs in carcinogenesis and the somatic mutation theory (SMT): the first (somatic mutation) occurs only after the second (onset of cancer) and, therefore, observed somatic mutations in most cancers appear well after the early cues of carcinogenesis are in place. It is no accident that mutations are increasingly being questioned as the causal event in the origin of the vast majority of cancers as clinical data show little support for this theory when compared against the metrics of patient outcomes. Ever since the discovery of the double helical structure of DNA, virtually all chronic diseases came to be viewed as causally linked to one degree or another to mutations, even though we now know that genes are not simply blueprints, but rather an assemblage of alphabets that can, under non-genetic influences, be used to assemble a business letter or a work of Shakespearean literature. A minority of all cancers is indeed caused by mutations but the SMT has been applied to all cancers, and even to chemical carcinogenesis, in the absence of hard evidence of causality. Herein, we review the 100 year story of SMT and aspects that show why genes are not just blueprints, how radiation and mutation are associated in a more nuanced view, the proposed risk of cancer and bad luck, and the in vitro and in vivo evidence for a new cancer paradigm. This paradigm is scientifically applicable for the majority of non-heritable cancers and consists of a six-step sequence for the origin of cancer. This new cancer paradigm proclaims that somatic mutations are epiphenomena or later events occurring after carcinogenesis is already underway. This serves not just as a plausible alternative to SMT and explains the origin of the majority of cancers, but also provides opportunities for early interventions and prevention of the onset of cancer as a disease.

Genomics, microRNA, epigenetics, and proteomics for future diagnosis, treatment and monitoring response in upper GI cancers.

One major objective for our evolving understanding in the treatment of cancers will be to address how a combination of diagnosis and treatment strategies can be used to integrate patient and tumor variables with an outcome-oriented approach. Such an approach, in a multimodal therapy setting, could identify those patients (1) who should undergo a defined treatment (personalized therapy) (2) in whom modifications of the multimodal therapy due to observed responses might lead to an improvement of the response and/or prognosis (individualized therapy), (3) who might not benefit from a particular toxic treatment regimen, and (4) who could be identified early on and thereby be spared the morbidity associated with such treatments. These strategies could lead in the direction of precision medicine and there is hope of integrating translational molecular data to improve cancer classifications. In order to achieve these goals, it is necessary to understand the key issues in different aspects of biotechnology to anticipate future directions of personalized and individualized diagnosis and multimodal treatment strategies. Providing an overview of translational data in cancers proved to be a challenge as different methods and techniques used to obtain molecular data are used and studies are based on different tumor entities with different tumor biology and prognoses as well as vastly different therapeutic approaches. The pros and cons of the available methodologies and the potential response data in genomics, microRNA, epigenetics and proteomics with a focus on upper gastrointestinal cancers are considered herein to allow for an understanding of where these technologies stand with respect to cancer diagnosis, prognosis and treatment.

Therapeutic approaches to gastroesophageal junction adenocarcinomas.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the distinction between adenocarcinomas above, below, or within the gastroesophageal junction; combined modality therapy; tumor markers for use in personalized medicine; PET-CT and endoscopic biopsies in the evaluation of response to neoadjuvant chemoradiation therapy; a standardized grading system for tumor regression in squamous cell cancer and adenocarcinoma; the experimental basis for new approaches to medical treatment; the criteria measuring response in esophageal cancer; and the impact of novel imaging on staging and response assessment.

Undervalued criteria in the evaluation of multimodal trials for upper GI cancers.

Global economies and their health systems face a huge challenge from cancer: 1 in 3 women and 1 in 2 men will develop cancer in their lifetime. In the less developed countries, the volume of cancer patients will overwhelm the existing healthcare systems. Even in developed regions, patients with upper gastrointestinal (GI) cancer usually present with locally advanced tumors that their prognosis is poor. A detailed knowledge of anatomy, embryology, epidemiology, tumor classifications and tumor growth is key understanding and evaluating the relevant research. We review undervalued criteria necessary to evaluate the response to multimodal therapy for upper GI cancers.

Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment.

The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling. Direct cell-cell communication involves both, self-self-communication (intracrine and autocrine), and adjacent communication with nearby cells (juxtacrine), which themselves are regulated by distinct pathways. Indirect intercellular communication involves local communication over short distances (paracrine and synaptic signaling) or over large distances via hormones (endocrine). The essential components of cell-cell communication involve communication junctions (Connexins, Plasmodesmata, Ion Channels, Chemical Synapses, and Pannexins), occluding junctions (Tight Junctions), and anchoring junctions (Adherens, Desmosomes, Focal Adhesions, and Hemidesmosomes). The communication pathways pass through junctions at physical cell-cell attachments, and they go, as well, through the extracellular matrix (ECM) via the different transmembrane adhesion proteins (Cadherins and Integrins). We have here reviewed cell-cell communication involving (1) the components of junctions and their dynamic interplay with the other aspects of communication, including (2) the tumor microenvironment and carcinogenesis, (3) coupling and migration, (4) the underlying cell-cell and sub-cellular communication mechanisms (signaling) of anticancer treatments, and finally, (5) aspects of recent research on cell-cell communication.

Epistemology of the origin of cancer: a new paradigm.

BACKGROUND: Carcinogenesis is widely thought to originate from somatic mutations and an inhibition of growth suppressors, followed by cell proliferation, tissue invasion, and risk of metastasis. Fewer than 10% of all cancers are hereditary; the ratio in gastric (1%), colorectal (3-5%) and breast (8%) cancers is even less. Cancers caused by infection are thought to constitute some 15% of the non-hereditary cancers. Those remaining, 70 to 80%, are called "sporadic," because they are essentially of unknown etiology. We propose a new paradigm for the origin of the majority of cancers. PRESENTATION OF HYPOTHESIS: Our paradigm postulates that cancer originates following a sequence of events that include (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. If we are correct, this paradigm would suggest that the majority of the findings in cancer genetics so far reported are either late events or are epiphenomena that occur after the appearance of the pre-cancerous niche. TESTING THE HYPOTHESIS: If, based on experimental and clinical findings presented here, this hypothesis is plausible, then the majority of findings in the genetics of cancer so far reported in the literature are late events or epiphenomena that could have occurred after the development of a PCN. Our model would make clear the need to establish preventive measures long before a cancer becomes clinically apparent. Future research should focus on the intermediate steps of our proposed sequence of events, which will enhance our understanding of the nature of carcinogenesis. Findings on inflammation and fibrosis would be given their warranted importance, with research in anticancer therapies focusing on suppressing the PCN state with very early intervention to detect and quantify any subclinical inflammatory change and to treat all levels of chronic inflammation and prevent fibrotic changes, and so avoid the transition from a normal cell to a cancer cell. IMPLICATION OF THE HYPOTHESIS: The paradigm proposed here, if proven, spells out a sequence of steps, one or more of which could be interdicted or modulated early in carcinogenesis to prevent or, at a minimum, slow down the progression of many cancers.

Time-dependent estimates of recurrence and survival in colon cancer: clinical decision support system tool development for adjuvant therapy and oncological outcome assessment.

Unanswered questions remain in determining which high-risk node-negative colon cancer (CC) cohorts benefit from adjuvant therapy and how it may differ in an equal access population. Machine-learned Bayesian Belief Networks (ml-BBNs) accurately estimate outcomes in CC, providing clinicians with Clinical Decision Support System (CDSS) tools to facilitate treatment planning. We evaluated ml-BBNs ability to estimate survival and recurrence in CC. We performed a retrospective analysis of registry data of patients with CC to train-test-crossvalidate ml-BBNs using the Department of Defense Automated Central Tumor Registry (January 1993 to December 2004). Cases with events or follow-up that passed quality control were stratified into 1-, 2-, 3-, and 5-year survival cohorts. ml-BBNs were trained using machine-learning algorithms and k-fold crossvalidation and receiver operating characteristic curve analysis used for validation. BBNs were comprised of 5301 patients and areas under the curve ranged from 0.85 to 0.90. Positive predictive values for recurrence and mortality ranged from 78 to 84 per cent and negative predictive values from 74 to 90 per cent by survival cohort. In the 12-month model alone, 1,132,462,080 unique rule sets allow physicians to predict individual recurrence/mortality estimates. Patients with Stage II (N0M0) CC benefit from chemotherapy at different rates. At one year, all patients older than 73 years of age with T2-4 tumors and abnormal carcinoembryonic antigen levels benefited, whereas at five years, all had relative reduction in mortality with the largest benefit amongst elderly, highest T-stage patients. ml-BBN can readily predict which high-risk patients benefit from adjuvant therapy. CDSS tools yield individualized, clinically relevant estimates of outcomes to assist clinicians in treatment planning.

Early detection of colorectal cancer recurrence in patients undergoing surgery with curative intent: current status and challenges.

Despite advances in neoadjuvant and adjuvant therapy, attention to proper surgical technique, and improved pathological staging for both the primary and metastatic lesions, almost half of all colorectal cancer patients will develop recurrent disease. More concerning, this includes ~25% of patients with theoretically curable node-negative, non-metastatic Stage I and II disease. Given the annual incidence of colorectal cancer, approximately 150,000 new patients are candidates each year for follow-up surveillance. When combined with the greater population already enrolled in a surveillance protocol, this translates to a tremendous number of patients at risk for recurrence. It is therefore imperative that strategies aim for detection of recurrence as early as possible to allow initiation of treatment that may still result in cure. Yet, controversy exists regarding the optimal surveillance strategy (high-intensity vs. traditional), ideal testing regimen, and overall effectiveness. While benefits may involve earlier detection of recurrence, psychological welfare improvement, and greater overall survival, this must be weighed against the potential disadvantages including more invasive tests, higher rates of reoperation, and increased costs. In this review, we will examine the current options available and challenges surrounding colorectal cancer surveillance and early detection of recurrence.

Future directions for the early detection of colorectal cancer recurrence.

Surgical resection remains a mainstay of treatment and is highly effective for localized colorectal cancer. However, ~30-40% of patients develop recurrence following surgery and 40-50% of recurrences are apparent within the first few years after initial surgical resection. Several variables factor into the ultimate outcome of these patients, including the extent of disease, tumor biology, and patient co-morbidities. Additionally, the time from initial treatment to the development of recurrence is strongly associated with overall survival, particularly in patients who recur within one year of their surgical resection. Current post-resection surveillance strategies involve physical examination, laboratory, endoscopic and imaging studies utilizing various high and low-intensity protocols. Ultimately, the goal is to detect recurrence as early as possible, and ideally in the asymptomatic localized phase, to allow initiation of treatment that may still result in cure. While current strategies have been effective, several efforts are evolving to improve our ability to identify recurrent disease at its earliest phase. Our aim with this article is to briefly review the options available and, more importantly, examine emerging and future options to assist in the early detection of colon and rectal cancer recurrence.

Imagine a world without cancer.

BACKGROUND: Since the "War on Cancer" was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type. DISCUSSION: Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long-term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patient's own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer-preventive variables, this approach is likely to result in an optimized anticancer strategy. SUMMARY: Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer.

Intraperitoneal chemotherapy and its evolving role in management of gastric cancer with peritoneal metastases.

Advanced gastric cancer (GC) has been recognized as lethal disease when peritoneal metastases (PM) occurred. There is no standard treatment for advanced GC with PM. Until 1980s, the therapeutic arena for these patients had remained stagnant, with no therapeutic approach having shown a survival gain in GC with PM. However, cytoreductive surgery (CRS) with peritonectomy procedures and intraperitoneal chemotherapy (IPC) promising new combined therapeutic approach to achieve disease control for GC with PM. The recent publications changed the GC with PM treatment landscape by providing an evidence that CRS and IPC led to prolongation in overall survival (OS). This review will provide an overview of the evolving role of CRS and IPC in the management of advanced GC with PM in the current era.

Current approaches and challenges for monitoring treatment response in colon and rectal cancer.

INTRODUCTION: With the advent of multidisciplinary and multimodality approaches to the management of colorectal cancer patients, there is an increasing need to define how we monitor response to novel therapies in these patients. Several factors ranging from the type of therapy used to the intrinsic biology of the tumor play a role in tumor response. All of these can aid in determining the ideal course of treatment, and may fluctuate over time, pending down-staging or progression of disease. Therefore, monitoring how disease responds to therapy requires standardization in order to ultimately optimize patient outcomes. Unfortunately, how best to do this remains a topic of debate among oncologists, pathologists, and colorectal surgeons. There may not be one single best approach. The goal of the present article is to shed some light on current approaches and challenges to monitoring treatment response for colorectal cancer. METHODS: A literature search was conducted utilizing PubMed and the OVID library. Key-word combinations included colorectal cancer metastases, neoadjuvant therapy, rectal cancer, imaging modalities, CEA, down-staging, tumor response, and biomarkers. Directed searches of the embedded references from the primary articles were also performed in selected circumstances. RESULTS: Pathologic examination of the post-treatment surgical specimen is the gold standard for monitoring response to therapy. Endoscopy is useful for evaluating local recurrence, but not in assessing tumor response outside of the limited information gained by direct examination of intra-lumenal lesions. Imaging is used to monitor tumors throughout the body for response, with CT, PET, and MRI employed in different circumstances. Overall, each has been validated in the monitoring of patients with colorectal cancer and residual tumors. CONCLUSION: Although there is no imaging or serum test to precisely correlate with a tumor's response to chemo- or radiation therapy, these modalities, when used in combination, can aid in allowing clinicians to adjust medical therapy, pursue operative intervention, or (in select cases) identify complete responders. Improvements are needed, however, as advances across multiple modalities could allow appropriate selection of patients for a close surveillance regimen in the absence of operative intervention.

Future directions for monitoring treatment response in colorectal cancer.

Treatment of advanced colon and rectal cancer has significantly evolved with the introduction of neoadjuvant chemoradiation therapy so much that, along with more effective chemotherapy regimens, surgery has been considered unnecessary among some institutions for select patients. The tumor response to these treatments has also improved and ultimately has been shown to have a direct effect on prognosis. Yet, the best way to monitor that response, whether clinically, radiologically, or with laboratory findings, remains controversial. The authors' aim is to briefly review the options available and, more importantly, examine emerging and future options to assist in monitoring treatment response in cases of locally advanced rectal cancer and metastatic colon cancer.

Evidence-based Guidelines for Precision Risk Stratification-Based Screening (PRSBS) for Colorectal Cancer: Lessons learned from the US Armed Forces: Consensus and Future Directions.

Colorectal cancer (CRC) is the third most common cause of cancer-related death in the United States (U.S.), with estimates of 143,460 new cases and 51,690 deaths for the year 2012. Numerous organizations have published guidelines for CRC screening; however, these numerical estimates of incidence and disease-specific mortality have remained stable from years prior. Technological, genetic profiling, molecular and surgical advances in our modern era should allow us to improve risk stratification of patients with CRC and identify those who may benefit from preventive measures, early aggressive treatment, alternative treatment strategies, and/or frequent surveillance for the early detection of disease recurrence. To better negotiate future economic constraints and enhance patient outcomes, ultimately, we propose to apply the principals of personalized and precise cancer care to risk-stratify patients for CRC screening (Precision Risk Stratification-Based Screening, PRSBS). We believe that genetic, molecular, ethnic and socioeconomic disparities impact oncological outcomes in general, those related to CRC, in particular. This document highlights evidence-based screening recommendations and risk stratification methods in response to our CRC working group private-public consensus meeting held in March 2012. Our aim was to address how we could improve CRC risk stratification-based screening, and to provide a vision for the future to achieving superior survival rates for patients diagnosed with CRC.

Serum-based DNA methylation biomarkers in colorectal cancer: potential for screening and early detection.

Colorectal cancer (CRC) is the third most common cause of cancer-related death in the United States. Early identification and treatment of pre-cancerous colorectal lesions, or node-negative CRC are highly effective interventions that substantially reduce disease-specific mortality. Colonoscopy remains a highly effective primary screening tool based on its excellent diagnostic accuracy, and its ability to remove pre-cancerous lesions. However, the nature of the procedure limits compliance with colonoscopy intended for population-based CRC screening. A significant advance in the screening and care of these patients could be realized by blood-based biomarkers, which could accurately identify patients at-risk for CRC development whom might benefit from early and/or more frequent surveillance for disease. We reviewed and herein discuss the potential for serum based DNA methylation biomarkers for screening and early detection of CRC.

Significance of infectious agents in colorectal cancer development.

Colorectal cancer (CRC) is a major burden to healthcare systems worldwide accounting for approximately one million of new cancer cases worldwide. Even though, CRC mortality has decreased over the last 20 years, it remains the third most common cause of cancer-related mortality, accounting for approximately 600,000 deaths in 2008 worldwide. A multitude of risk factors have been linked to CRC, including hereditary factors, environmental factors and inflammatory syndromes affecting the gastrointestinal tract. Recently, various pathogens were added to the growing list of risk factors for a number of common epithelial cancers, but despite the multitude of correlative studies, only suggestions remain about the possible relationship between selected viruses and bacteria of interest and the CRC risk. United States military service members are exposed to various risk factors impacting the incidence of cancer development. These exposures are often different from that of many sectors of the civilian population. Thereby, cancer risk identification, screening and early detection are imperative for both the military health care beneficiaries and the population as a whole. In this review, we will focus on several pathogens and their potential roles in development of CRC, highlighting the clinical trials evaluating this correlation and provide our personal opinion about the importance of risk reduction, health promotion and disease prevention for military health care beneficiaries.