Summary of contribution of hypertension to HF in recent SSA studies.
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\r\n\tThe aim of this book project is to compile the updated research work on medicinal applications of noble metal complexes mainly focusing the structure activity relationship of metal complexes with targeting biological components.
Cardiomyopathies are common in Africa. Common causes of myocardial diseases in the region are hypertensive heart disease, endemic cardiomyopathies such as dilated cardiomyopathy, endomyocardial fibrosis, and peripartum cardiomyopathy and most recently heart diseases due to HIV/AIDS and ischemic cardiomyopathy. They are often associated with high morbidity and mortality due to late presentation, lack of modern day treatment available in high-income countries, as well poverty, which limits access to healthcare. Figure 1 shows the common causes of heart failure (HF) in sub-Saharan Africa (SSA) based on a recent survey of acute HF in the region [1]. The chapter deals with hypertensive heart disease (hypertensive cardiomyopathy) peripartum cardiomyopathy and HIV-associated cardiomyopathy.
Etiological risk factors for heart failure in sub-Saharan Africa. (Adapted from Damasceno et al. HHF = Hypertensive heart failure, DCM = Dilated cardiomyopathy, RHD = Rheumatic heart disease, IHD = Ischemic heart disease, PPCM = Peripartum cardiomyopathy, PDX = Pericardial diseases, HIV_CM = HIV associated cardiomyopathy, EMF = Endomyocardial fibrosis.
More than 30% of adults in SSA have hypertension. The prevalence rate is among the world highest. Worse still, the region has some of the world’s lowest rates of hypertension awareness, treatment, and control. About 66% of the people are not aware, 82% are not treated and 93% are uncontrolled. In the year 2010, the age standardized prevalence of hypertension in adults aged 20-years and above was estimated as 36.9 and 36.3% for men and women, respectively (this is compared to 20.9 and 20.3%, 10 years earlier). This translates to 64.8 and 63.8 million men and women with elevated blood pressure in 2010 (compared to 25.5 and 24.9 million hypertensive men and women in the year 2000).
\nIn a recent systematic analysis of population-based studies of hypertension in SSA, the pooled prevalence in the region rose from 19.7% in 1990 to 30.8% in 2010. It is estimated that there were about 54.6 million people with hypertension in Africa in 1990. This rose to 130.2 million cases in 2010. It is also projected that by the year 2030, there will be about 216.8 million cases of hypertension in the region [2].
\nHypertension is the commonest and strongest risk factor for cardiovascular disease (CVD) in SSA [3]. It is also the commonest cause of disability and death from non-communicable diseases (NCDs) in the region [4]. The condition often manifests in young and middle aged adults in their productive years [4]. It is estimated to cause over 500,000 adult deaths annually and about 10-million years of life lost. Over 50% of heart disease and HF in the region is attributed to elevated blood pressure.
\nAccording to the African Union, hypertension is one of the greatest health challenges in adults in Africa after HIV/AIDS [4]. Recent data indicate that hypertension is rising in SSA at a faster rate compared to other regions of the world [5, 6]. This has been attributed to that adoption of western lifestyle, diet and culture, urbanization, urban migration from rural areas, ageing of the population, and increasing use of cigarettes and alcohol [3, 5–7].
\nIt has been demonstrated that a chronic hyperadrenergic state is common among African hypertensives and may be responsible for the high prevalence of hypertension observed in Africans [8].
Heart disease secondary to elevated blood pressure (hypertensive heart disease), which may manifest in the following ways:
\nLV diastolic dysfunction is common in hypertensive subjects in the region [9–12]. About 62% of hypertensive individuals have various degrees of LV diastolic dysfunction compared to 12% of normal subjects [9, 13]. Diastolic dysfunction is worse in those with concentric LV geometry [9] as well as in individuals at risk of obstructive sleep apnea [14]. Diastolic dysfunction also occurs in offspring of hypertensive subjects [15–17].
Right ventricular systolic dysfunction has been reported in about 62% of a cohort of hypertensive patients [18, 19]. RV diastolic dysfunction may be an early clue to the development of hypertensive heart disease in Africans [19].
Absolute and indexed left atrial diameter, area, or volume is increased in African hypertensive subjects [20, 21]. Compared to their age- and sex-matched controls, hypertensive Africans show statistically significant left atrial structural and functional alterations [21].
Electrocardiographic LVH occurs in 18–56% of hypertensive Africans depending on the criteria employed for the diagnosis. Sokolow-Lyon criteria appear to have the best sensitivity, while Estes score and Cornell criteria have the best specificity. Some workers in the region have proposed new criteria for ECG diagnosis of LVH in Africans especially in obese subjects [22–28]. ECG LVH with strain pattern is associated with worse LV structure and function in hypertensive Africans [29, 30].
\nThe prevalence of echocardiographic LVH ranges from 30.9 to 74%. This, however, depends on the threshold used for the indexation of LV mass. Adebiyi et al. report 61–74% prevalence of abnormal LV geometry in hospital patients at the University College Hospital, Ibadan, Nigeria [31].
\nIn a similar study in Northern Tanzania [32], 70% of the hypertensive subjects have abnormal LV geometry. The distribution of the abnormal LV geometric patterns is 19.8, 28.2, and 22% for concentric remodeling, concentric hypertrophy, and eccentric LVH, respectively. The best yield appears to be when LV mass is indexed to height raised to the power of 2.7 (allomeric growth rate of the heart). Age, systolic blood pressure, and duration of hypertension are independent predictors of LVH.
\nLV systolic dysfunction (LVSD) occurs in 18.1% (9.6, 3.7, and 4.8% for mild, moderate, and severe LVSD, respectively) of hypertensive Africans [33]. The independent predictors of LVSD are LV mass, body mass index, and male gender. Ojji et al. [34] report LVSD in 6.7% (mild—3.5%, moderate—2.3%, and severe—0.9%) of 1943 hypertensive subjects and LV dysfunction is associated with older age, male sex, presence of diabetes mellitus, and some indices of the LV structure.
\nThe Tei index (index of global myocardial performance) is significantly higher in hypertensive Africans compared to controls. The index increases with severity of LVSD. It is negatively related to the LVEF.
RV systolic dysfunction occurs in about in 32% of hypertensive subjects seen in tertiary centers in the region [18, 35, 36]. RVSD is worse in subjects with eccentric LV geometry. LVEF appears to be the main determinant of RVSD. Recently, Ojji et al. [37] reported RVSD in 44.5% of 611 hypertensive subjects. RVSD estimated by TAPSE <15mm is associated with worse prognosis. LVEF and right atrial area are the main determinants of RVSD.
Hypertensive HF (HHF) is a common and major form of presentation of HF in Africa. Table 1 shows the contribution of hypertension in the etiology of HHF in SSA. In the Heart of Soweto study [38], 54% of hypertensive patients visit the hospital on account of this disorder. This devastating form of HHD is often associated with concurrent LVH, renal dysfunction, and anemia. In a study of 180 HHF patients in Ghana, the mean age of presentation is 63.6 years (range-24–88 years) and seen more often in women. The mean systolic blood pressure at presentation is 162.4 mmHg. Shortness of breath, easy fatigability, and palpitation are common symptoms while pulmonary edema and displaced apex beat are the common signs. Cardiomegaly on chest radiography is present in 75.6%. ECG-LVH or ECHO-LVH occur in 75.6 and 83.3%, respectively. About 62% have heart failure with preserved ejection fraction HFpEF [39].
S. No. | Author/Publication Year | Country | HHF (%) |
---|---|---|---|
1 | Damasceno [1], 2012 | 9 countries | 45.4 |
2 | Stewart [41], 2008 | South Africa (Soweto) | 33.3 |
3 | Ojji [42], 2009 | Nigeria(Abuja) | 62.6 |
4 | Ojji [43], 2013 | Nigeria(Abuja) | 60.6 |
5 | Ogah [44], 2014 | Nigeria(Abeokuta) | 78.5 |
6 | Karaye [45], 2008 | Nigeria(Kano) | 57 |
7 | Laabes [46], 2008 | Nigeria(Jos) | 44.1 |
8 | Onwuchekwa [47], 2009 | Nigeria(Port-Harcourt) | 56.3 |
9 | Adewuya [48], 2006 | Nigeria(Ile-Ife) | 54 |
10 | Yonga [49], 2010 | Kenya | 64 |
11 | Kingue [50], 2005 | Cameroon (Urban) | 54.5 |
12 | Tantchou [51], 2011 | Cameroon (rural) | 15 |
13 | Soliman [52], 2008 | Malawi | 24 |
14 | Kuule [53], 2009 | Uganda | 24.2 |
15 | Okello [54], 2014 | Uganda | 9.1 |
17 | Owusu [55], 2013 | Ghana (Outpatients-Kumasi) | 45 |
18 | Owusu [56], 2006 | Ghana (In-patients-Kumasi) | 42.6 |
19 | Soliman [52], 2011 | Sudan | 28 |
20 | Habte [57], 2010 | Ethiopia | 24.2 |
21 | Makubi [58], 2014 | Tanzania | 45 |
Summary of contribution of hypertension to HF in recent SSA studies.
In Nigeria, HHF is more common in men (56%). The mean age of presentation is 58.4 and 60.6 years in men and women, respectively. Over 80% present in NYHA class III and IV. HFpEF is present in about 35% of cases. The median length of hospital stay is about 9-days while 3.4% die while on admission. A 30-, 90-, and 180-day mortality rates of 0.9, 3.5, and 11.7%, respectively have been reported. Renal dysfunction appears to be the main independent predictor of mortality [40].
\nTable 2 shows the characteristics of African patients with HHF compared with similar patients in other parts of the world.
Characteristics | Ogah et al. [40] (n = 320) | Stewart et al. [41] (n = 281) | Nieminen et al. [59] (n = 200) | Spinar et al. [60] (n = 179) | Venskutonyte et al. [61] (n = 65) |
---|---|---|---|---|---|
Female (%) | 42.5 | 61 | 39.6 | 65.4 | 33.3 |
Mean age (yrs) | 59.3 | 61 | 69.8 | 74.8 | 65.5 |
Denovo HF (%) | 85.6 | NA | 37.3 | 74.3 | 66.7 |
NYHA III+IV (%) | 82.2 | 29 | NA | 34.0 | NA |
Previous history of hypertension (%) | 90.6 | 100 | 94.6 | 94.3 | 100 |
Diabetes mellitus (%) | 12.2 | 14 | 34.5 | 43.1 | 33.3 |
Previous MI or CAD (%) | 0.3 | 1.0 | 53.8 | 26.4 | 46.7 |
COPD (%) | 2.5 | NA | 18.0 | 17.8 | 26.7 |
Stroke or TIA in history (%) | 0.3 | 12 | 16.0 | 26.4 | 20 |
Atrial fibrillation (%) | 12.8 | 9 | 37.7 | 19.0 | 46.7 |
Mean systolic BP(mmHg) | 144 | 140 | NA | 198 | NA |
Mean diastolic BP(mmHg) | 91 | 80 | NA | 100 | NA |
Heart rate (beats/min) | 96 | NA | NA | 93 | NA |
Body mass index (kg/m2) | 24.2 | NA | NA | 28.0 | 33.9 |
Hospitalization for HF within last 12 months (%) | 82.2 | NA | NA | 45.1 | 46.6 |
Renal failure (%) | 14.4 | 27 | 18.7 | NA | NA |
Anemia (%) | 11.5 | 10 | 11.3 | NA | NA |
Infection (%) | 63.4 | NA | 15.6 | NA | 13.3 |
Noncompliance with therapy (%) | 74.1 | NA | 21.9 | NA | 66.7 |
ACE inhibitors (%) | 99.1 | NA | NA | 71.3 | NA |
Beta-blockers (%) | 2.7 | NA | NA | 77.0 | NA |
Calcium antagonists (%) | 30.6 | NA | NA | 51.1 | NA |
Diuretics (%) | 86.9 | NA | NA | 88.5 | NA |
Spironolactone (%) | 81.3 | NA | NA | 36.2 | NA |
Digoxin (%) | 73.1 | NA | NS | 13.8 | NA |
LVEDD (mm) | 55 | 46 | 56 | NA | 50* |
Mean ejection fraction | 42.7 | 53 | 44 | 55 | 50.5 |
LA (mm) | 47 | NA | 45 | NA | 42* |
Mitral regurgitation (%) | 79.1 | 7 | 77.6 | NA | 100 |
Tricuspid regurgitation (%) | 60.8 | 6 | 53.7 | NA | 93.3 |
LOS days, median | 9 | NA | 8 | NA | 13 |
Intrahospital mortality (%) | 3.4 | NA | 1.5 | 2.2 | 6.6 |
Comparison of our findings with similar studies in other parts of the world.
Abbreviation: HOS = Heart of Soweto Study, EHFS II = European Heart Failure Survey II, AHEAD = Acute Heart Failure Database, HF = Heart Failure, NYHA = New York Heart Association, MI = Myocardial Infarction, CAD = Coronary Artery Disease, COPD = Chronic Obstructive Pulmonary Disease, TIA = Transient Ischemic Attack, BP = Blood Pressure, LVEDD = Left Ventricular End-Diastolic Diameter, LA = Left Atrium, LOS = Length of Hospital Stay
Hypertension is a common cause of pressure overload of the left ventricle. LVH develops as an adaptation to this overload. Hypertensive patient with ECG LVH has 10-fold higher risk of developing HF [41]. There is increased wall thickness at the expense of chamber volume in LVH due to hypertrophy of the myocyte and by a parallel alignment of the sarcomere [42]. Specific hypertensive cardiomyopathy has been proposed. This cardiomyopathy has been divided into four stages: in stage 1, there is diastolic dysfunction, which is present in 20–30% of patients. This is common in elderly women, hypertensive diabetics, and ischemic heart disease patients [43]. LV diastolic dysfunction precedes systolic HF and is therefore a more common mechanism of HF in hypertension. Stage 2 is hypertension with impaired LV relaxation abnormalities, while grade 4 is dilated cardiomyopathy with LV systolic dysfunction. It has been shown that apoptosis may be responsible for the reduction of myocyte mass that accompanies progression from compensated hypertrophy to HF.
\nSeveral theories have been proposed to explain the relationship between LVH and HF. This includes changes in the coronary microcirculation, which leads to poor myocardial perfusion, impaired cardiac function, loss of contractile protein, and thus reduced cardiac contractility [44]. The second theory is increased LV pressure overload, which leads to ventricular dilatation and reduced cardiac output [45].
\nFinally, LVH in hypertension is governed by different loading conditions, which involve both hormonal and paracrine factors such as the sympathetic nervous system and renin-angiotensin-aldosterone axis [46].
Peripartum cardiomyopathy (PPCM) is a form of heart disease characterized by “the development of HF in the last month of pregnancy or within the first 5 months postpartum in the absence of any other determinable cause for cardiac failure and in the absence of demonstrable heart disease before the last month of pregnancy, and bears echocardiographic evidence of left ventricular systolic dysfunction” [62]. In addition, the diagnosis of the condition requires evidence of impaired LV systolic function by echocardiography (LVEF < 45% or LVFS < 30%). LV dilation is common although in some patients, LV dimension may be normal but the LV systolic function is impaired [62, 63].
In terms of epidemiology, PPCM is common in developing and poor communities. The incidence is 1/1000 in most parts of low- and middle-income countries [64]. However, very high incidence has been reported from Northern Nigeria (1/100 live births) [65–69] and Haiti (1/300 live births) [70, 71]. The incidence in high-income countries is in the range of 1/3000–1/4000 deliveries [64]. There has been an increase in the awareness of the disease worldwide with the establishment of a global registry.
\nPPCM is responsible for about 1.5% cases of HF in the Heart of Soweto study [41], 1.3% in the Abeokuta HF registry [44] and 3.2% in the Abuja Heart Study [42]. It is still the most prevalent form of cardiomyopathy (54.6%) in Northern Nigeria [45].
Risk factors for the development of this cardiac disorder include low socioeconomic status, women of African descent (although PPCM is a global disease), young pregnant women, multiparity, multiple pregnancy, and longer period of breast feeding [64]. However, recent prospectively collected data on PPCM do not support strong association with older age of pregnancy, multiparity, twin pregnancy, gestational hypertension, and the use of tocolytic agents [72].
Shortness of breath is common form of presentation. Other common clinical features include, cardiomegaly, tachycardia, pulmonary rales, high blood pressure and dysrhythmias. Dyspnea, cough, orthopnea, palpitation, hemoptysis, chest pain, and abdominal pain are other common features. Most patients in SSA present in NYHA class III/IV [68, 72]. Thromboembolic complications are common in the form of pulmonary embolism and stroke from mural thrombus [73, 74].
\nThere are some differences between PPCM and hypertensive heart failure of pregnancy (HHFP). Patients with HHFP are more likely to present in the last trimester, while PPCM patients are more likely to present within the first month of the postpartum period. Family history of hypertension and history of hypertension in previous pregnancy is commoner in HHFP. Twin pregnancy and presence of leg edema are more common in PPCM. Blood pressures are generally higher in HHFP and they are also more likely to have basal rales. Furthermore, functional murmurs (tricuspid and mitral regurgitation) occur more often in PPCM compared to HHFP [75].
Arrhythmias are also common. In severe cases, anemia and renal dysfunction may be present. The liver enzymes may be normal or mildly raised from hepatic congestion. Some authors in Benin republic, Mali and Nigeria have reported the association of PPCM with micronutrient deficiencies, e.g., selenium, ceruloplasmin [76–78]. LV function and mortality in PPCM patients with HIV infection and those without have been found not to differ significantly [79].
\nThe 12-leads ECG often show sinus rhythm, ST-T changes are common, which resolves after the postpartum. Ventricular arrhythmia occurs in about 20% [80–83].
\nEchocardiography is the diagnostic procedure of choice. Useful for the evaluation of LV systolic function (EF < 45%), and diastolic function as well as assessment for presence of intramural thrombus formation. The mean LV internal dimension in diastole is often about 6 cm; however, some patients have nondilated LV. Where available in SSA, magnetic resonance imaging helps in the detection of myocardial fibrosis with late enhancement imaging. It also helps in the assessment function, shape, size, as well as contents. Immunohistochemistry of biopsy specimen from patient with PPCM is not different from that of idiopathic DCM. Similar viral particles, e.g., coxsackie, encephalomyelocarditis, parvovirus B19, adenoviruses, herpes simplex virus, Ebstein-Burr virus, and cytomegalovirus DNA. Inflammatory markers such as tumor necrosis factor alpha (TNF-alpha) and C-reactive protein levels are raised in both conditions and cannot be used to differentiate one from the other. However, peculiar to PPCM are some immune activation processes, e.g., elevated levels of marker of apoptosis-FAS/APO 1. This has been shown to predict prognosis [84].
More recently, Sliwa and her colleagues have shown the role of cleavage of prolactin in the pathogenesis of PPCM. A 16-KDa fragment of prolactin may induce myocardial damage [85]. This has provided a new option of blocking prolactin secretion with bromocriptine in the treatment of PPCM.
Full recovery of LV function occurs in about half of PPCM patients [72]. About 25% recover by the end of 6 months and around 10–15% die within 6 months. Long-term prospective follow-up studies show that overall recovery occurs in about 25% of patients and this mostly occurs in the first 18–24 months of diagnosis [79].
\nIn recent time, there has been an increased awareness of this condition, and it has been recognized in the guidelines of the American College of Cardiology and European Society of Cardiology. Large global or continental registries of PPCM exist and many centers in SSA are participating. The European society of Cardiology has recently released a position paper on the disorder [62].
SSA contributes about 69 and 90% of the global adult and childhood HIV/AIDS burden. HIV-associated cardiomyopathy is therefore a significant contributor to CVD morbidity and mortality in the region [86, 87].
\nThe true prevalence of HIV-associated cardiomyopathy is unknown. The prevalence of HIV-associated cardiomyopathy in the pre-HAART era was about 50%. The incidence of any cardiac abnormality in HIV-infected individuals was 55% over a 7-year period [88–90]. It was common in young persons with CD4 count of <100 cells/mm3, lower socioeconomic class, longer duration of the infection, higher viral load, and advanced stage of the disease [89, 91]. In-hospital mortality was 15% [89].
\nBecause of the availability of HAART, the prevalence has reduced by about 50% in high-income countries [92]. However, in low-income countries (where most of the countries in SSA belong to), the prevalence of the condition has increased by 32% due to poor and limited access to HAART as well the impact of malnutrition [93].
\nEchocardiographic studies have reported prevalence ranging from 5% (in Nigeria) to 57% in Burkina Faso [89, 91, 94]. Differences may be due to study design and lack of common definition of the disorder [95].
\nIn the Heart of Soweto study, about 9.7% of the cohort were HIV infected, 54% of who were on HAART [41, 81]. They were younger, had lower blood pressure and body mass index, and higher heart rate compared to the general cohort. HIV associated HF was the commonest diagnosis. The mean LVEF was 46% and common in women who were also about 6-years younger than the men. HIV patients who had HF had lower CD4 count compared to those who did not have. They were also more likely to have right-heart failure and valve dysfunction [96].
\nAbout 2.6% of HF cases in the THESU-HF survey were due to HIV infection. They were younger by 10–15 years and were less often smokers, hypertensive, or diabetic. They had larger LV dimensions but had similar LVEF compared to the general cohort [1]. The findings from the Heart of Soweto and the THESUS-HF survey are similar to more recent observational studies in the region. The prevalence is in the range of 1–5% [67, 73, 74]. It is often diagnosed in the third decade of life and more often in women. Both systolic and diastolic HF are common (about 30%).
The proposed mechanism in the pathogenesis of HIV-associated cardiomyopathy include the direct myocardial invasion by the HIV, post-viral autoimmunity, immune system dysregulation, adverse effect of the viral protein, endothelial dysfunction, transcriptional activation of cellular genes, and beta-adrenergic dysregulation. Others include HIV-immunosuppression-related myocarditis due to opportunistic infection with toxoplasmosis, cryptococcus, and mycobacteria. Myocardial dysfunction as a result of systemic effects of sepsis may also play a role. Some of the anti-retroviral medications may play a role in the pathogenesis. Nucleoside reverse transcriptase inhibitors cause mitochondrial damage by inhibiting mitochondrial DNA polymerase. Zalcitabine is thought to exhibit the greatest toxicity among this group [97]. Zidovudine causes cardiac and skeletal myopathy [98].
\nMalnutrition especially selenium deficiency is another possible mechanism. Selenium has an antioxidant property and protects against endothelial dysfunction. Its deficiency is associated with cardiac dysfunction. Due to soil composition and agricultural practices in the region, selenium deficiency is common and 285 of the SSA population are at risk of selenium deficiency. Selenium deficiency has been demonstrated in HIV patients [99]. Selenium supplementation has also been shown to improve cardiac function in some studies [100].
\nHeavy alcohol use and smoking have also been implicated especially in high-income countries [101]. This was not demonstrated in a Rwandan study [101].
\nThe role of genetic factor has not been demonstrated in Africa. “ The mitochondrial DNA T16189C polymorphism, with a homopolymeric C-tract of 10-12 cystosines—a putative genetic risk factor for idiopathic dilated cardiomyopathy in the African and British populations—was not associated with HIV-associated cardiomyopathy in a South-African case control study” [102].
Cancer cells arise in non-malignant tissue due to the sequential acquisition of molecular alterations that drive proliferation, permit the evasion of growth suppression and apoptosis signals and promote angiogenesis, invasion and metastasis [1]. This process is stochastic, and over time the tumour continues to evolve in a dynamic manner, generating a group of cells harbouring different genetic and epigenetic features [2]. The resulting heterogeneity is the basis of tumour evolution and leads to the selection of tumour cells. These cells often present with rewired signalling networks and often oncogene addiction [3].
\nThe uncontrolled growth of cancer cells can in part be explained by their aberrant gene expression patterns. While most cancer genes are characterized as either oncogenes or tumour suppressors based on their typical behaviour in tumours, some genes display dual oncogenic and tumour suppressive functions [4, 5]. The majority of these genes encode multiple isoforms, which are further post-translationally modified and form a variety of protein complexes, generating a context-dependent cellular network [6]. In diploid organisms, gain-of-function (GOF) mutations in oncogenes are typically dominant (single events are sufficient to promote tumourigenesis), while loss-of-function alterations are recessive in TSGs (requires two inactivation events) [7]. For example, for a TSG with dual oncogenic roles, one gain-of-function mutation can potentially cease its tumour suppressive function and turn on oncogenic signalling [5].
\nRecently, genes with both oncogenic and tumour-suppressive functions were described across 12 main cancer types using The Cancer Genome Atlas (TCGA) database [5]. Using a text mining approach, the authors identified genes mainly represented by kinases (e.g. BCR, CHEK2, MAP2K4, NTRK3 and SYK) or transcription factors (e.g. BRCA1, EZH2, NOTCH1, NOTCH2, STAT3 and TP53) and evaluated them at the genomic and gene expression levels. Using an in silico analysis, it was shown that genes with dual functions interact with more partners and are more important hub-genes in protein-protein interaction networks.
\nIn this chapter, we discuss TSGs with both tumour suppressive and oncogenic functions in lung cancer.
\nLung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide [8]. In the United States, lung cancer accounts for 13.5% of all new cancer cases and 25.3% of all cancer deaths. The five-year survival rate is dismal, with only 18.6% of patients surviving 5 years [9]. The majority of lung cancer cases (approximately 80%) are attributed to cigarette smoking [10]. About 10–25% of cases occur in people who have never smoked [11]. The aetiology behind these cases is most likely a combination of genetic factors, as well as the effects of exposure to environmental carcinogens such as asbestos, radon gas or other forms of pollution [12].
\nLung cancer is classified according to histological type. There are two major types: small cell lung cancer (SCLC), which accounts for 15–20% of lung cancer patients, and non-small cell lung cancer (NSCLC), comprising the remaining 80–85% (Figure 1) [13]. SCLC, primarily originating from the central airways, is thought to be derived from neuroendocrine cells [14]. NSCLC is composed of three major histological subtypes: adenocarcinoma (LUAD), squamous cell carcinoma (LUSC) and large cell carcinoma (LCC). LUAD is the most common, accounting for approximately 40% of all lung cases [15]. LUAD typically arises from glandular epithelium, from bronchioalveolar stem cells, club (Clara) cells or type II pneumocytes in the lung periphery [13]. LUAD is also the predominant subtype that arises in patients who have never smoked [15]. LUSC develops primarily in the central airways and segmental bronchi, strongly associates with a history of smoking and accounts for approximately 20% of all lung cancer cases. LCC may arise anywhere in the lung and are classified as tumours without general features associated with SCLC, LUAD or LUSC [13].
\nHistological classification of lung cancer. (A) Lung cancer histological types. (B) Location of the tumours and cell origins. SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; LCC, large cell carcinoma.
Beyond the histological heterogeneity of lung cancer, genomic studies of large cohorts have uncovered the complex molecular landscape of lung tumours. Indeed, it has been observed that a wide variety of oncogenes and TSGs can be altered in lung cancer, and these molecular events are vastly different between histological subtypes [16, 17].
\nClinical studies have shown that molecularly defined lung cancer subgroups can correlate with characteristics such as ethnicity [18], smoking history [19], treatment sensitivity [20] or prognosis [21]. Many of the commonly identified gain-of-function alterations in proto-oncogenes have been actively investigated for therapeutic purposes. For example, EGFR, ALK, ROS1, BRAF, MET, RET and HER2 are routinely assessed in the clinic to offer targeted therapy for eligible LUAD patients [22].
\nThree TSGs are frequently mutated in all three major lung cancer subtypes: TP53, LRP1B and CSMD3. Other TSGs of particular interest in lung cancer are as follows RB1 and CREBBP in SCLC, KEAP1 and STK11 in LUAD, CDKN2A in LUSC, NOTCH1 and PTEN in both SCLC and LUSC and NF1 in both LUAD and LUSC (Figure 2). Mutations in these TSGs are usually mutually exclusive, indicating that individual genes are capable of driving lung cancer progression.
\nMutational frequency of TSGs in small cell lung cancer (SCLC; n = 110) [16], lung adenocarcinoma (LUAD; n = 660) [23] and lung squamous cell carcinoma (LUSC; n = 484) [23]. TSGs were defined according to COSMIC Cancer Gene Census (https://cancer.sanger.ac.uk/census) and mutation frequency of the most commonly disrupted TSGs in these subtypes of lung cancer were retrieved using cBioPortal (http://www.cbioportal.org/).
Several TSGs in lung cancer have also been shown to behave as oncogenes, depending on the molecular context and/or the mechanism by which they are altered (Table 1). Among them are TP53, NFIB, members of the NOTCH family, NKX2-1, NFE2L2, as well as some non-coding RNAs (MALAT1, mir-125, and mir-378), which will be discussed in detail below.
\nGene | \nMain function | \nRole as TSG | \nRole as oncogene | \n
---|---|---|---|
TP53 | \nTF: regulates cell cycle, DNA repair, senescence and apoptosis | \nTSG in several tissues: frequently lost through mutations [24] | \nMissense mutations confer gain-of-function oncogenic properties [31] | \n
NFIB | \nTF: crucial in lung development | \nUnderexpressed in NSCLC and associated with poor survival in LUAD [32] | \nAmplified and OE in SCLC: inducing chromatin reprogramming during metastasis [33] | \n
NOTCH1/NOTCH2 | \nTransmembrane receptors: proliferation, differentiation and survival | \nInactivated by inhibitor ligands and through mutations, especially in SCLC [34] | \nMaintains stem cell features; promotes proliferation in LUAD [35] | \n
NFE2L2 | \nTF: cellular defense mechanism against oxidative stress | \nProtects lung tissue against exposure to oxidative stress [36] | \nMutational activation: aids cells to escape from endogenous tumour suppression [37] | \n
NKX2-1 | \nTF: essential for lung development | \nActs as a TSG in KRAS-driven p53-mutant LUAD [38] | \nEnhanced oncogenic signals in EGFR-driven LUAD [39] | \n
STK11 | \nSerine-threonine kinase: regulation of energetic metabolism and cell polarity | \nMutational inactivation promotes cancer development [40] | \nOE maintains metabolic homeostasis and attenuates oxidative stress [40] | \n
TGFB | \nCytokine: regulates development, differentiation and homeostasis | \nExpression loss leads to growth arrest in early-stage lung and other cancers [41] | \nOE promotes tumour growth in advanced cancer stages [42] | \n
TUSC3 | \nEndoplasmic reticulum protein in magnesium uptake, glycosylation and embryonic development | \nHypermethylation; expression loss in NSCLC; inhibits cell proliferation and promotes apoptosis [43] | \nOE in NSCLC accelerates cancer growth; induces EMT [44] | \n
WT1 | \nTF: role in urogenital system development | \nLoss of function enhances cell viability and proliferation in Wilms’ tumour [45] | \nOE promotes survival in KRAS-mutated NSCLC [46] | \n
MALAT1 | \nLong non-coding RNA | \nOE reduces invasiveness in PTEN expressing tumours [47] | \nOE associated with chemotherapy resistance in NSCLC [48] | \n
miR-125b | \nmicroRNA | \nOE induces apoptosis [49] | \nOE promotes metastasis [50] | \n
miR-378 | \nmicroRNA | \nOE reverses chemoresistance to cisplatin in LUAD [51] | \nOE is associated with invasion and brain metastasis [52] | \n
Main TSGs with dual functions reported in lung cancer.
TF, transcription factor; OE, overexpression; EMT, epithelial-mesenchymal transition. Numbers in brackets refer to the list of reference.
TP53 is a well-known TSG, representing the most common somatically mutated gene in human cancer, especially in lung tumours [24]. The classic functions of the encoded p53 protein are cell cycle regulation, DNA repair, senescence mediated by stress, apoptosis and angiogenesis. These functions mainly occur through the binding of a p53 tetramer to the promoter of target genes [25]. In many cancer types, TP53 mutation is associated with poor prognosis, including local and distant metastases events, resistance to treatment and decreased survival [26, 27].
\nDespite having a reputation as a ‘guardian of the genome’, recent work has shown that activating TP53 alterations can act to promote cancer development and progression [25, 28]. Depending on the location of the mutation within the TP53 gene, protein structure and subsequent DNA binding activity can be lost or altered, resulting in either loss or gain of function [25]. In contrast to the majority of TSGs, TP53 is not commonly inactivated by deletions or truncating mutations. Indeed, 74% of mutations within the TP53 locus are missense point mutations, which can be found in proteins in human tumours [25]. In fact, altered TP53 was initially considered as a cancer antigen with putative oncogenic properties [25]. Together, this highlights the dichotomous role of TP53 disruptions, in that both the loss of wild-type p53 and gain-of-function mutations can provide a growth advantage to tumours [28].
\nLung cancer is commonly associated with tobacco use, where the prolonged exposure to carcinogens damages the DNA of the exposed cells. These alterations are especially enriched in missense mutations in TP53, leading to GOF-p53 [29]. The oncogenic GOF mutation in p53 was previously shown to be related with the inactivation of AMP-activated protein kinase (AMPK) signalling in head and neck cancer and another tobacco-related cancer [30]. AMPK is a master regulator of metabolic homeostasis and GOF-mutated p53 is able to physically interact and inhibit AMPK, stimulating aerobic glycolysis under energetic stress conditions and leading to invasive growth.
\nIn lung cancer mouse models, prevention of tumour formation by inhibiting GOF p53 mutants has been demonstrated [53]. Although the highly aberrant genomes in p53-mutated tumours should lead to unfeasible mitosis, these mutations facilitate the survival and proliferation of these cells through stabilizing replication forks and promoting micronuclei arrangement [31].
\nGOF p53 mutants are most likely involved in multiple mechanisms that coordinate tumour progression. For example, GOF-p53 (R175H, R273H and D281G) was demonstrated to upregulate CXCL5, CXCL8 and CXCL12 through its transcription factor activity, promoting migration of lung cancer cell lines [54]. CXCL5 expression was shown to be elevated in human lung tumour samples harbouring GOF-p53, and its inhibition could reverse cell motility in lung cancer and melanoma cell lines [54]. In NSCLC, it was recently reported that GOF-p53 can physically interact with HIF-1 and binds to the SWI/SNF chromatin remodelling complex, inducing the expression of hypoxia-responsive genes [55]. Importantly, specific extracellular matrix components are upregulated by this process and mediate pro-tumourigenic features in NSCLC [55].
\nNuclear factor I (NFI) is a transcription factor family, comprising NFIA, NFIB, NFIC and NFIX, that plays important roles in normal development and in numerous diseases [56]. These proteins bind to specific DNA sequences leading to repression or activation of gene expression in a context-dependent manner, regulating cell differentiation and proliferation through their target genes [57]. NFIB, in particular, has been implicated in a wide range of malignancies, being described as both an oncogene and a potential TSG [58].
\nUsing an in vivo model, it was demonstrated that NFIB is a metastatic driver in SCLC, inducing global chromatin reprogramming during metastasis [33]. The authors isolated tumour cells from primary and metastatic sites of genetically engineered mice, and using genome-wide analysis, they showed a pronounced increase in chromatin accessibility during tumour progression, resulting from NFIB copy number amplifications. Interestingly, the distal regions that became accessible upon NFIB upregulation were similar to open regions found in neural tissue. Recently, the same group described two metastatic models in SCLC, one dependent and other independent of NFIB amplification [59]. NFIB was likewise reported as amplified and/or overexpressed in melanoma [60], breast [61], oesophagus [62] and salivary gland malignancies [63].
\nA gene fusion involving NFIB (MYB-NFIB) is frequently found in adenoid cystic carcinomas from salivary glands [64] and in adenoid cystic carcinoma from other topologies [65]. Despite the putative oncogenic function of NFIB, studies have focused on its fusion partner MYB as the main oncogenic driver in these cancers [66]. Given the fact that other fusion partners of NFIB have been reported in adenoid cystic carcinomas [67] and that MYB-NFIB fusions lead to NFIB truncation [68], NFIB may have a possible independent role as a TSG in these malignancies.
\nWhile the MYB-NFIB fusion is not observed in lung cancers, NFIB is frequently underexpressed in NSCLC tissues [32] and during epithelial-to-mesenchymal transition in NSCLC cell lines [69]. NFIB is an essential transcriptional factor in lung development [70] and was demonstrated to be targeted by many microRNAs that recapitulate their foetal lung expression patterns in NSCLC [32]. Lower expression of this gene was associated with shorter overall survival, less-differentiated tumour features and repressed expression of cell differentiation markers in LUAD patients [32]. Therefore, contrary to the established oncogenic role of NFIB in SCLC, these observations suggest a tumour suppressive role in NSCLC.
\nThe Notch signalling pathway is important in the regulation of cell fate during embryogenesis and maintenance of homeostasis in adult tissues [71]. It includes Notch receptors (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) and ligands from the DSL family, which suppress or induce tumour-related mechanisms under specific cellular contexts [71].
\nIn SCLC, Notch signalling is frequently inactivated by either a mutation in Notch receptors or the overexpression of ligands that inhibit downstream signalling [34]. Despite this potential role as a TSG, Notch signalling in lung tumours is complex, as it has also been shown to be related to chemoresistance in SCLC [72]. In addition, the overactivation of this pathway through several mechanisms acts like an oncogene in LUAD by preserving stem cell features and promoting proliferation [35, 73]. Notch1 expression is required in Kras-driven LUAD carcinogenesis, suppressing apoptosis via the p53 pathway [35]. The inhibition of the Notch pathway is able to restrain lung cancer stem cell maintenance, which is characterized by subpopulations of cells expressing aldehyde dehydrogenase [74].
\nConversely, loss-of-function mutations of Notch receptors generating truncated receptors imply a TSG role in LUSC [75]. Although functional studies to further corroborate this hypothesis are still needed, reports in other squamous cell carcinomas substantiate the idea that the inactivation of this signalling pathway promotes tumourigenesis [76].
\nNkx2-1 is a homeobox-containing transcription factor that is essential for lung development and is expressed in type II pneumocytes and bronchiolar cells in adults [77]. It is expressed in 40–50% of lung cancers and is amplified and overexpressed in 6–11% of LUAD [78].
\nNkx2-1 acts as a lineage-specific oncogene in some LUAD cases [79], enhancing cell viability and proliferation in lung cancer cell lines [78]. This function relies on the activation of (i) the pro-survival PI3K-AKT pathway, through ROR1 kinase-dependent c-Src activation as well as maintaining the EGFR-ERBB3 association [80], and (ii) LMO3, a member of the LMO family of oncogenes that is translocated in T-ALL [81].
\nOn the other hand, Nkx2-1 expression has been associated with good patient outcome [82] and the loss of Nkx2-1 expression was associated with the aggressive behaviour of NSCLCs [83]. Mechanistically, tumour suppressive functions of Nkx2-1 in lung adenocarcinoma rely on the restriction of cell motility, invasion and metastatic ability, through the inhibition of the TGF-β [41] and IKK-B/NFk-B [39] pathways. The dual role of Nkx2-1 is dependent on EGFR, KRAS and TP53 status in LUAD: NKX2-1 acts as a TSG in KRAS-driven and TP53-mutant tumours, whereas it enhances EGFR-driven tumourigenesis [84, 85].
\nNFE2L2 encodes a transcription factor that regulates proteins involved in cellular defense mechanisms against metabolic, xenobiotic and oxidative stress [86]. NFE2L2 has been often considered a TSG due to its protective role against genome-damaging agents, the higher propensity to cancer development in NFE2L2-deficient mice and its protective effects in cancer chemoprevention [87].
\nDue to the constant exposure to oxidative stress in the lung, the NFE2L2 pathway is important to guarantee the genomic stability of these cells [88]. However, once transformation of normal to cancer cells occurs, NFE2L2 favours tumour development by acting to protect against oxidative stress resulting from the tumour microenvironment and exposure to genotoxic agents during patient treatment [86]. In fact, mutations in NFE2L2 and KEAP1, an important member of the NFE2L2 signalling, are very common and mutually exclusive in NSCLC [89]. Curiously, a recent study demonstrated that lung cancer patients presenting NFE2L2 or KEAP1 mutations are highly resistant to chemotherapy [89]. However, the relation between the NFE2L2 pathway and treatment response prediction needs further investigation.
\nWhile large-scale genomic sequencing efforts have uncovered an invaluable number of genetic alterations related to cancer biology, in the past, they were commonly focused on the 2% of the genome that encodes protein [90]. In the last decade, non-coding RNA transcripts have been shown to have important regulatory functions in normal and disease biology [91]. Indeed, many non-coding genes have been shown to play tumour-suppressive or oncogenic roles in numerous cancer types [92].
\nMetastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was one of the first cancer-related long non-coding RNAs to be described [93]. MALAT1 is broadly expressed in normal cells, where it has been shown to regulate the alternative splicing of pre-mRNAs by changing the distribution of splicing regulators in nuclear speckles [94]. MALAT1 was primarily identified as an oncogenic transcript in lung cancer and has since been widely considered a marker of metastasis, poor patient survival [93] and chemotherapy resistance in NSCLC [48]. Mechanistically, MALAT1 has been shown to promote carcinogenesis through P53 deacetylation [95] and enhance cell migration through Akt/mTOR signalling [96] and TGF-β-induced endothelial-to-mesenchymal transition [97]. Conversely, MALAT1 has also been shown to reduce invasiveness by modulating the expression of EpCAM and ITGB4 in PTEN-expressing tumours [47] and by downregulation of MMP2 and inactivation of ERK/MAPK signalling [98]. MALAT1 also binds the nuclear p65/p50 heterodimer and thus inhibits NF-κB-dependent pathways [99] and is thought to be involved in the response to DNA damage [100]. Furthermore, MALAT1 reduces the invasiveness of cerebral metastases by sustaining the blood-brain barrier [101]. MALAT1 expression and subcellular location is finely tuned through various regulatory mechanisms [102], which may drive its pro- or anti-tumour effects [103]. Analysis of the dual role of MALAT1 highlights not only the complexity of non-coding RNA function but also their relevance to broad areas of cancer biology and management.
\nMicroRNAs (miRNAs) are short transcripts that typically regulate coding genes post-transcriptionally through direct interaction with mRNA transcripts. Many are deregulated in lung cancer [104], where they have documented tumour-suppressive and oncogenic roles [105]. For example, miRNA-125b has been shown to have a multifaceted function as a tumour suppressor and oncogene, being underexpressed in bladder [106] and ovarian cancer [107] and overexpressed in glioma [108] and prostate cancer [109]. It was shown that miRNA-125b induces apoptosis in cancer cell lines exposed to nutrient starvation and chemotherapy, including in lung cancer [49]. On the other hand, miRNA-125b may also function as an oncogene in NSCLC, as it is able to promote metastasis by targeting TP53INP1 [50]. In addition, inhibition of miR-125b can also decrease the invasive potential and leads to cell cycle arrest and apoptosis in NSCLC [110]. Similarly, miR-378 was reported to be overexpressed in lung cancer and other tumour types, inducing cell migration, invasion and tumour angiogenesis [111]. However, it was previously demonstrated that upregulation of this miRNA sensitizes lung cancer cell lines to cisplatin [51].
\nHere, we summarize the commonly disrupted genes in lung cancer with dual roles as both tumour suppressors and oncogenes. These conflicting roles are a result from the complexity of biological pathways and the heterogeneity of cancer cells.
\nMost of the current molecular therapies are based on hyperactivated oncogene inhibitors. In lung cancer, only a fraction of the cases exhibit alterations in targetable genes, such as EGFR, BRAF and MET mutations and ALK, RET and ROS1 fusions [112]. Therefore, there is an urgent need for the development of novel therapeutic strategies exploiting non-oncogene alterations of lung tumour cells.
\nConsidering that TSGs are found altered more frequently than oncogenes in human tumours [113], the existence of TSGs with dual oncogenic roles opens a new window of opportunities for the development of new targeted therapies. However, therapeutic action against TSGs remains challenging, as many are not amenable to current pharmacologic inactivation strategies. Most of the TSGs are not a kinase that can be pharmacologically blocked and are not located at the cell surface to be targeted by an antibody.
\nIn summary, there is an unmet need to clarify the ambiguity found within genes, both coding and non-coding, with both pro- and anti-tumour functions. Broadening our understanding of these features may enable the development of novel and specific therapeutic strategies that consider both molecular and tissue contexts.
\nThis work was supported by grants from the Canadian Institutes for Health Research (CIHR FDN-143345) and scholarships from CIHR, the BC Cancer Foundation, the Ligue nationale contre le cancer, the Fonds de Recherche en Santé Respiratoire (appel d’offres 2018 emis en commun avec la Fondation du Souffle), the Fondation Charles Nicolle and the São Paulo Research Foundation (FAPESP 2015/17707-5 and 2018/06138-8). D.D.B.S. and E.A.M. are Vanier Canada Scholars.
\nThe authors have no conflicts to declare.
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
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\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
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\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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