Microbial Crosstalk with Immune System: New Insights in Therapeutics

Our body is not sterile and harbors enumerable microflora that are now being understood to play a complex role in immune regulation and shaping of the immune system in a continuous and dynamic way. In 8 chapters, Microbial Crosstalk with Immune System: New Insights in Therapeutics provides an overall introduction with special focus on how the immune system which is specifically geared to get rid of non-self-antigens, allows numerous microbes to colonize the human body. In the presence of microbes there are several observations that suggest that there are multiple roles that are played by these microbes in tumor progression and shaping of our immune system which is explained at length in subsequent chapters.

Microbial Crosstalk with Immune System: New Insights in Therapeutics discusses the emerging mechanisms of immune-therapeutics as well as its limitations while emphasizing the potential role of microbes in shaping immune-therapeutic and evolving novel strategies to deal with any limitations.

• Focuses on the modulation of immune system by the microbiome, thus affecting cancer prognosis
• Discusses various current research strategies in the field that are still in experimental stages. enabling readers to gain a perspective on the ongoing research in the field
• Gives insight into the emerging mechanisms of immune-therapeutics and its limitations
• Emphasizes the potential role of microbes in shaping immune-therapeutics

• Language: English
• Publisher: Academic Press
• Release date: Jul 26, 2022
• ISBN: 9780323995795

Book preview

Front Cover for Microbial Crosstalk with Immune System - New Insights in Therapeutics - 1st edition - by Asmita Das

Microbial Crosstalk with Immune System

New Insights in Therapeutics

Edited by

Asmita Das

Department of Biotechnology, Delhi Technological University, New Delhi, India

Table of Contents

Cover image

Title page

Copyright

List of contributors

Chapter 1. Introduction

Abstract

1.1 Host immune response against infections

1.2 Increased tolerization in gut

1.3 Dynamics of gut microbiota and its dependency on external factors

1.4 Cancer and its hallmarks

1.5 Involvement of immune system in cancer

1.6 Microbiota and cancer

References

Chapter 2. Significance of the normal microflora of the body

Abstract

2.1 Introduction

2.2 Normal microflora

2.3 Human microbiome

2.4 Conclusion

References

Chapter 3. Immunological paradox for maintaining normal flora: it is all by design, not by chance

Abstract

3.1 Microflora in the development of immune system

3.2 Immune system tolerance of microflora

3.3 Protective role of short-chain fatty acids in inflammation and cancer prevalence

3.4 Microflora and adaptive immune system

3.5 Environmental factors altering microflora and influencing immune system

3.6 Microflora dysbiosis in disease and impact on immune system

3.7 Conclusion

Acknowledgments

References

Chapter 4. Cancer prognosis and immune system

Abstract

4.1 Introduction

4.2 Defining pathology

4.3 Molecular pathology

4.4 Need for molecular diagnosis

4.5 Techniques involved in molecular diagnosis

4.6 Pathological and molecular aspects of different cancers

4.7 Artificial intelligence in studying cancer pathology

4.8 Immune system: innate and adaptive immunity

4.9 Conclusion

References

Chapter 5. Human microbiota: role in cancer progression and therapy

Abstract

5.1 Introduction

5.2 Relationship between human microbiota and cancer

5.3 Conventional therapies used for treatment of cancer

5.4 Role of microbiota in cancer progression

5.5 Role of microbiota in cancer regression and therapy

5.6 Challenges, gaps, and future perspectives

5.7 Conclusion

Acknowledgments

References

Chapter 6. Microflora impacts immune system and its antitumor function

Abstract

6.1 Introduction

6.2 Cancer immunotherapy

6.3 Diverse microflora in humans

6.4 Microbiota, disease development, and effect on immune system

6.5 Microbes and autoimmune diseases

6.6 Evidence for the antitumor function of microflora

6.7 Conclusion

References

Chapter 7. Cancer therapeutics and gut microflora

Abstract

7.1 Cancer: biology and treatment

7.2 Gut microbiota: an organ in itself!

7.3 Gut microbiota, immune system, and cancer development

7.4 Role of gut microbiota in cancer therapy

7.5 Conclusion

Conflict of interest

Author contributions

Funding

References

Chapter 8. Missing rungs in cancer therapeutics and strategies to climb them

Abstract

8.1 Surgery–radiation–chemo-therapy

8.2 Genomically targeted therapy

8.3 Cancer immunotherapy

8.4 Upcoming therapies

8.5 Advancements in therapeutic procedure

8.6 Microbes in cancer therapeutics

8.7 Biobanking of cancer samples

8.8 Centralized data curation

8.9 Affordability of cancer treatment

References

Index

Copyright

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List of contributors

Shruti Ahlawat

Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India

Department of Microbiology, Faculty of Allied Health Sciences, SGT University, Gurugram, Haryana, India

Apoorva,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Aprajita,     University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India

Asha,     Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India

Preeti Chand,     Special Centre for Nano Science and AIRF, Jawaharlal Nehru University, New Delhi, India

Asmita Das,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Muskaan Dhingra,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Saksham Garg,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Neelima Gupta,     Department of Animal Sciences, Dr. Harisingh Gaur University, Sagar, Madhya Pradesh, India

Varsha Gupta,     Department of Life Sciences, Chhatrapati Shahu Ji Maharaj University, Kanpur, Uttar Pradesh, India

Kashish Kosta,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Ritika Luthra,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Shayon Mahalanobis,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Deeksha Mehtani,     Cellular and Molecular Immunology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

Tarunya Menon,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Jaya Prakash,     Orthopaedics Department, Community Health Centre, Kanpur, Uttar Pradesh, India

Tulika Prasad,     Special Centre for Nano Science and AIRF, Jawaharlal Nehru University, New Delhi, India

Niti Puri,     Cellular and Molecular Immunology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

Anam Rais,     Special Centre for Nano Science and AIRF, Jawaharlal Nehru University, New Delhi, India

Priyanka Rawat,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Krishna Kant Sharma,     Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India

Nikita Sharma,     Department of Biotechnology, Delhi Technological University, New Delhi, India

Rinu Sharma,     University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India

Baishnab Charan Tripathy

School of Life Sciences, Jawaharlal Nehru University, New Delhi, India

School of Biotechnology, Sharda University, Ghaziabad, Uttar Pradesh, India

Chapter 1

Introduction

Asmita Das and Saksham Garg,    Department of Biotechnology, Delhi Technological University, New Delhi, India

Abstract

There is a long-standing relationship between trillions of microbes and human beings. Microbes and humans have coevolved, involving synergistic, commensal, and pathogenic interaction with microbes. The sustenance of a huge diversity of microbes that are harbored in the human body poses a significant question to the success of the self–nonself discrimination by our immune system and elimination of any potential antigens. The evolutionary coexistence of microbes in the human body and the development of a robust immune system prompt the evolutionary benefit of this tolerized response of the immune system toward specific microbes. There is an emerging understanding of the role of microbes in shaping our immune system that is crucial for tumor progression and autoimmunity. With advances in microbial research through sequencing, metabolomics, proteomics, and bioinformatics approaches, the deeper and more intricate role of microbes has been brought to focus. The vast gut microbiota is now thought to play a very sophisticated and intricately balanced role in determining prognosis of various health conditions. The microbiota is not only responsible for metabolic processes but also a role in progression and regression of complex ailments such as cancer. Cancer is caused by genetic aberrations and certain hallmarks are used to define cancer and its stages. There is a very complex interplay in place between the three components, microbiota, cancer, and host immune system. Microbiota being a part of tumor microenvironment can modulate the immunological responses, drug efficacies and play a crucial role in immunotherapies.

Keywords

Infections; immune system; cancer hallmarks; microbiota; tumor microenvironment

1.1 Host immune response against infections

All living beings on this planet face the threat of infections that are inevitable for any particular individual. Any physical measure taken is usually futile. To survive natural selection and perpetuation of species, all living organisms have developed some form of immune system over the course of evolution. Humans have developed the most complex immune system of them all, with a wide variety of cells, molecules, receptors, and organs acting in a concerted war strategy to mitigate infections and harmful cells from the body. It utilizes a significant amount of resources and produces large quantity of cells daily. Humans and other animals survive in a surrounding heavily doped with pathogenic and nonpathogenic microbes, and variety of toxic and allergenic substances. It is the constant surveillance offered by immune system that enables a harmonized survival and continuation of species. Although human history is filled with emerging deadly infections causing epidemics and pandemics and infectious diseases continue to evolve, the immune system also continues to evolve and mitigate the infections in service of human health.

Immune system can be classified into two different branches that are closely interconnected but differ in their response to infections, namely, innate and adaptive immunity. In a nutshell, innate system comprises all the components which are produced by germ-line genes in their mature form to serve the host and is considered to possess broad spectrum specificity for self and nonself distinction. While adaptive immune system is very specific in its response which is encoded by the genes that are rearranged and exhibit clonal selection by antigenic epitopes. The innate immune response is a barrier response in general providing physical barriers controlling the entry of pathogenic material, mucous layers throughout different orifice act as traps for invading pathogens, highly effective cell types like natural killer (NK) cell, macrophages, etc. that play crucial role in viral infections and tumor transformations and mediating the relay of information to adaptive immune system. The active immune cells of innate response recognize the pathogens through some conserved regions called microbial-associated molecular patterns (MAMPs) using their surface and endosomal pattern recognition receptors conferring a robust but limited specificity immune response [1]. Adaptive response confers a very high specificity toward the antigens and possesses antigen-specific T-cell and B-cell surface receptors which are capable of recognizing potentially every different antigen that we shall come across in our life time, thanks to the few hundred diverse genes encoding for millions of receptor types. Keeping a memory of the antigen type is the unique characteristic feature of adaptive immune system which facilitates a faster and more robust response for the subsequent exposure to the same antigenic epitope in future [2]. This belief although has been challenged recently by few studies, which have found memory response in NK cells as well [3]. Conventionally, innate and adaptive immune systems are described and thought to be separate and contrasting; however, they act simultaneously, innate cell acts as first line of defense along with presenting the pathogenic antigens to stimulate adaptive immune components for a more prominent response. Adaptive immune cells once activated act either by cytotoxic method or by humoral response mediated using antibodies via clonal expansion. Additionally, antigen-specific cells signal the recruitment of highly effective innate cells to gain complete control over the foreign particles and invading pathogen. Fundamentally, both arms of immune system are essentially interlinked, coordinated, and important for the protection and effective mitigation of infectious agents from the host system [4].

Despite having developed such a profound and orchestrated response against microbes, human body has always sheltered a vast community of microbes. Human body is laden with microbes all over, almost every surface harbors them. This long and standing association is clearly indicative of some evolutionary advantageous links. Studies have shown them to impact our tissue development [5], diet [6], behavior [7], and also pathogen resistance [8,9]. Strain or microbes are specific to each body site with a very dynamic nature which vastly makes the host–microbe interaction a complex biological system. Microbes and the mammalian immune system portray a highly coevolved characteristic to an extent that evidences show that microbes have sculpted certain cells and tissues of our immune system. Microbes are long appreciated for their involvement in lymphoid tissue organization. Germ-free mice are generally devoid of isolated lymphoid follicles [5]. Microbial-induced TLR-MyD88 mechanisms are important for the reconstruction of intestinal epithelium [10] and also promoted production of antimicrobial peptides like RegIIIɣ [11]. Individual cell types are also influenced by microbes particularly T cell subsets in both gut and systemic regions. Bacterial presence is known to expand the population of Th17 and Th1 cells [12,13]. Some bacterium like Clostridial strains direct differentiation of Treg cells by inducing interleukin 10 (IL-10) expression. The balance between the Treg and effector cells is crucial in determining the mucosal layer response [13]. Recent studies also have extended the role of microbes to the subset of natural killer cells, invariant natural killer T cells [14]. Although immune system is the one keeping a check on microbial communities all over the body, the coevolution with microbes has led immune system to develop mechanisms. Together with all these findings, it can be concluded that commensal bacteria have an impact in every aspect of our functioning and are advantageous to us which explains their presence and why the immune system actively shows tolerization to some microbes.

1.2 Increased tolerization in gut

In general, microbes are always considered pathogenic; however, humans have a symbiotic relationship with over a 100 trillion microbes in the intestine [15]. These microorganisms are able to develop such tight and symbiotic relationship that they facilitate digestive processes. Some authors have also claimed the microbiome as an organ in the human system. Their existence, however, constantly stimulates the gut-associated lymphoid tissues (GALT). GALT is continuously exposed to immeasurable amounts of antigens produced by gut microorganisms leads to the phenomenon called as oral tolerance [16]. The phenomenon is extremely essential in forming a healthy gut and to prevent any allergic response against the innocuous food antigens. GALT enables the balance by preventing the inflammatory pathways against microbiota and food-derived antigens. The tolerization however in no sense diminishes the systemic immune response to the invading or harmful pathogens by mounting an effective immune response [16]. Oral tolerance was first studies in rodents and now is being described in humans as well [17,18]. The evaluation of oral tolerance resulted in decreased production of cytokines and T-cell proliferative activities. The phenomenon suppresses a wide range of immune responses by preventing inflammation and enables the homeostasis between the human gut and the microbiota.

In the immunological perspective, our commensal microbes are extremely crucial for human intestine. It is their recognition that triggers GALT either for the stimulatory effect or for the tolerogenic response. The recognition here fundamental aspect. Among all pathogen recognizing receptors, toll-like receptors (TLRs) are expressed on antigen-presenting cells (APCs) [19]. Their expression on the surface defines the recognition of antigen and subsequently the immune response. Gut epithelium often sees a downregulation of TLR2 and TLR4 that are primarily responsible for lipopolysaccharide (LPS) and peptidoglycan tolerance [20,21]. A stable gut microbiota resists a TLR5-induced flagellin-derived response; however, introduction of a pathogenic entity like Salmonella drives an acute proinflammatory response. Gram-negative bacteria in the gut become tolergenic due to their LPS being unable to stimulate TLR9 receptor [22].

A number of mechanisms have been proposed which may facilitate this tolerance and enable the microbes to grow and develop in harmony. GALT can downregulate the TLR-dependent immune regulation by decreasing the TLR expression, releasing soluble receptors such as TLR2 and TLR4. Deploying a decoy receptor such as ST2 ligand and IL-1 also comes in handy. The regulation of MyD88 pathway, Toll-interacting protein, and TNF-related apoptosis-inducing ligand receptor all are being utilized by the innate system to inhibit the immunological inflammatory response [23–25].

A growing piece of evidence also elucidates microbiota modulating the adaptive immune response as well. It is well known that the folds in the lamina propria harbor a wide range of cells such as innate cells, myeloid cells, and T cells, which maintain this delicate cellular circuit. Microbes are capable of modulating the regulatory T cells to establish an effective tolerization in the gut environment. This prevents many food allergy, gut hypersensitivity, and conditions like autoimmunity and celiac syndrome. Germ-free mice models have helped in understanding the process and pathways. Colonization by commensal species such as Clostridia and Bacteroidales fragilis in germ-free mice induced a transforming growth factor beta-rich (TGF-β) environment which supported the proliferation of CD4+FoxP3+Treg cells and FoxP3+ Treg cells, respectively. Tregs production resulted in a cytokine-rich environment (IL-10) that was antiinflammatory in nature [26–28].

Quite recently, mononuclear phagocytes (MNPs) are considered to be holding a switch in mediating the tolergenic and inflammatory immune response using the CX3CR1 receptor [29]. In many studies, germ-free mice have elucidated the role of microbes in exhibiting and formation of tolerization response in gut. Kim’s group explains that the CX3CR1+ MNPs maintain the homeostasis (Fig. 1.1). They have showed that the gut microbes limit the translocation of CX3CR1+ MNPs to the mesenteric lymph nodes and MNPs promote the barrier repair process [30]. Along with these findings, they also demonstrated that the MNPs with CX3CR1 expression were able to modulate and limit the T helper cell proliferation in gut microenvironment and promote the Treg cell proliferation. Loss of CX3CR1+ cells resulted in increased pathogenicity and decreased number of Treg cells. The depletion of microbiota using antibiotics confirmed the role of microbes as the oral tolerance by MNPs was not established and led to Salmonella-specific T cell response along with increased interferon gamma (IFN-ɣ) production which increases the permeability of gut membrane allowing bacteria to proliferate and cause infection. The increased number of cases of inflammatory bowel disorders, which are arising due to microbial dysregulation in the gut positively sheds light on importance of healthy microbes in gut environment. Again with the collective efforts of both innate and adaptive immune system and with the help of commensal microbes, the tolerization response is mediated and conferred, while the balance is very delicate and is crucial in effective immune response to potential pathogens [31].

Figure 1.1 Tolerance relay forwarded by CX3CR1+ mononuclear phagocytes induced by gut microbiota and dietary antigens.

1.3 Dynamics of gut microbiota and its dependency on external factors

The symbiotic relationship between the microbiome and humans is long known but the extent of this codependent relationship has come to light recently with Human Microbiome project providing comprehensible data factoring about 2172 species in the gut. Primitive studies estimated about 10 times more bacterial cells as compared to human cells in our body but recent high-throughput studies suggested a 1:1 ratio in cell count but a figure of 100-fold greater microbial genome than human genome [32]. Human genome expresses ~23,000 genes, while the residing microbiota expresses around 3 million genes collectively [33]. This diversity is not static but is always dynamic with regard to the external environmental conditions such as air pollution, sanitary conditions, and antibiotic treatment, and according to various stages of life.

1.3.1 Dynamic nature across various stages of life

As human body grows and evolves according to the stage in life and environment, it is exposed to, in a similar way, microbiota is also influenced by our growth (Table 1.1). Children, adults, and elderly have hugely diverse microbiome present.

Table 1.1

1.3.1.1 Prenatal development

Contrary to the thinking that gut microbiota develops postparturition of the baby. The first and the early exposure to microbes happens in the womb itself. Microbes have the ability to get transferred to the developing baby from maternal blood via meconium [34], amniotic fluid [35], and placenta [36]. Marked and labeled Enterococcus faecium was observed in the new born fecal matter, which was orally administered to the mother in her gestation period [37].

1.3.1.2 Parturition

The primary microbiota highly differs between the cesarean delivered and vaginally delivered babies and it evolves eventually and respectively. In the vaginally born babies, Prevotella and Lactobacillus bacteria are found quite prevalent. Interestingly, the diversity was similar to the mother’s vaginal microbiota [38].

The babies being delivered using surgical methods like C-section/cesarean had Streptococcus, Cornybacterium, and Propionibacterium as their inhabiting bacteria that are mostly prevalent on the skin surface of the mother [39].

1.3.1.3 Infant stage

The feeding pattern of an infant has a direct relationship with the further evolution and development of gut microbiota. This difference arises from the fact that infants can be either breast fed or given an oral formula-based diet [40]. The variation in feeding pattern leads to the diversification of commensal bacteria in the gut. Infants on their mother’s milk diet dominate with Lactobacillus and Bifidiobacterium species [41], while the formula fed diet enables a microbiota comprising of Enterococcus, Bacteriodes, Streptococcus, Clostridia, and Enterobacteria [42].

1.3.1.4 Adult stage

Studies have come to a conclusion describing a diversified commensal gut microbiota. One study took subjects from 0 to 70 years of age and depicted that the diversification was higher in children than in adults. In the adult stage, a number of factors decide the overall gut microbiota and its variation and are always dynamic to the conditions provided to it. It is concluded, however, that after 3-year children start to exhibit an adult-like composition [43].

1.3.2 Other factors affecting gut microbiota

1.3.2.1 Antibiotics

Antibiotics as therapeutics presented themselves as a great discovery and they are being investigated continuously for various ailments and pathogens but with the extensive and popularized usage of antibiotics, antibiotic resistance has risen as a problem [44]. Antibiotics primarily work via three mechanisms: first, by interfering with the cell wall disruption or formation mechanism, secondly by disrupting the proteins, and thirdly by causing a deoxyribonucleic acid (DNA) damage to limit the growth of bacteria. The intake of antibiotics often results in the dysbiosis in the gut since the antibiotic not only kills the targeted pathogen but also results in mitigation of healthy commensal bacterium [45]. This phenomenon can be particularly observed in case of ciprofloxacin administration. The said drug prescribed in urinary tract infection caused by Escherichia coli but results in the removal of E. coli and generally all gram-negative bacteria from all the regions in passes through. Usually, the target pathogen becomes resistant to the drug which as result will sweep out the nonresistant commensal bacteria species [46].

1.3.2.2 Air pollution

Recent advances have shown air pollutants to alter the gut microbiota. A dramatic shift in concentration of gut microbes was observed in the mice which was fed with a feed mixed with particulate matter. The relative concentration of Bacteriodetes, Firmicutes, and Verrucomicrobia differed [47]. This difference caused resulted in decreased production of butyrate which in turn caused damage to the intestinal epithelium and disrupted the barrier [48].

1.3.2.3 Xenobiotics

Xenobiotics are foreign substances which enter in our system from natural sources like from plant and animal products and from artificial sources as well which include drug, chemicals, and pesticides. These substances are known to cause an alteration in either functioning or relative quantities of the gut microbiota acting as health hazards [49].

1.3.2.4 Probiotics

While most of the external factors disturb the natural balance. Probiotics bacteria that we usually consume through food and they in general sense have a positive impact on our health [50]. Strains such as Lactobacillus and Bifidobacterium are considered to be probiotics. They are capable of producing short-chain fatty acids such as lactate and butyrate that have both direct and indirect positive impact on a healthy gut. Production of butyrate fortifies the barrier and induced the epithelial cells to grow and manage barrier repair process. Probiotics usually serve their functionality by stimulating and immune system to produce immunoglobulin A- and B-defensin resulting in suppression of proliferation of harmful gut bacteria. The mechanism is mediated by cytokines and through proliferation of T cells and epithelial cells [51–53].

1.4 Cancer and its hallmarks

Cancer can be described as a disorder of somatic cell arising due to the accumulation of several mutations on genetic level. It can be characterized by constant cell division with a gradual increase in tumor size, a disorganized complex, and invasion. A cell indicative of tumor development losses its capability to regulate proliferative properties by mutation in genes. These mutations affect the genes controlling the cell cycle and also affect the tumor-suppressing and proto-oncogenes. This results in aberration in regulation of cell-cycle processes and contributes to the malignancy of the tumor. We have a vast scientific knowledge of cancer and the numbers continuously rise with each advancement in the field of therapeutics, diagnostics, and patient care. To suffice and understand such broad area of cancer, it has been characterized by six hallmarks [54].

1.4.1 Self-sufficiency in signaling growth factors

All normal cells are dependent on growth factors for their mitotic growth and proliferation. Entering into the mitotic phase require a very distinctive class of signals such as growth factors, extracellular matrix components, and adhesion molecules. In normal conditions, this process happens in a single region and the responsibility is given to a few cells. But in cancerous mass, oncogenes have been seen to mimic these growth factor in several ways. The altered expression of oncogenes leads tumor cells to generate their own cell growth factors thus liberating their dependency on microenvironment normal cells to produce the growth factors. Contradictory to normal cells, in a tumor mass, it is observed that all constituent cells acquire the ability to synthesize growth factors thus resulting in a formation of a positive feedback loop within the cancerous tissue mass. This is evident from production of PDGF in glioblastoma and tumor necrotic factor alpha (TNF-α) in sarcoma cases [54]. To maximize the utilization and be hyperresponsive to surrounding growth factors, cancers upregulate the growth receptors. While human epidermal growth factor receptor-2 is upregulated in stomach and mammary carcinoma epidermal growth factor receptor is over expressed in brain, breast, and stomach tumors [55]. In a molecular perspective, integrins are crucial in signal transduction for the cell division process to take place. Cancer is able to hijack that as well and employs the progrowth integrins that do not showcase any restrictive properties enabling cancer growth and proliferation. This hostile takeover activates Ras-associated cascade, which is at the center of whole mechanism to make cancer cells autonomous in regard to production of growth factors and facilitate the division as well as the growth of individual cell [56].

1.4.2 Insensitivity to antigrowth signals

After the mitotic division, the cell receives either of the two fate. It either can either be force into quiescent stage from which they can reemerge and divide later on which appropriate signals are given or they can undergo differentiation forming a highly specific functional cell of an organ system. The fate is facilitated by the antigrowth signals that operate in a similar manner as their positive counter parts. The cancer cells evade these cell signaling pathways. During the G1 phase of cell cycle, retinoblastoma proteins (pRb) act as the antiproliferative signals. Cancer cells have devised multiple ways to disrupt the pRb pathway allowing them to proliferate and enter the cell cycle process continuously. While this process in specific to cancer type, there are few pathways that are observed in almost all cancer types. pRb pathway is exclusively maintained by TGF-β so cancer cells become a negative responder to TGF-β by either making dysfunction or mutant receptors. Smad4 acts a translocator of TGF-β and is usually eliminated in cancer cells. The aberrant cells also reduce or hamper the production of tumor suppressive proteins like p15. Another efficient strategy devised by cancer cells is the activation of c-Myc oncogene. In normal conditions, a complex of Mad–Max produces an antiproliferative signal by forcing cells to differentiate but in cancer due to c-Myc production, Myc–Max complex is formed that tips the scale in the cancer’s favor by compromising the differentiation process [57–59].

1.4.3 Evading apoptosis

Apoptosis is referred to the programmed cell death and to cancer that is a biggest threat to its survival. In a normal cell, apoptosis is solely mediated by mitochondria through the release of cytochrome c in the cytoplasm. To regulate the release of cytochrome c, we have subset of both proapoptotic (Bid, Bim, Bak, Bax) and antiapoptotic (Bcl-2, Bcl-XL, Bcl-W) family of proteins. Forced expression of Bcl-2 and Bcl-XL along with c-Myc gene resulted in formation of B cell lymphomas in mice model. Apoptosis is initiated in response to damaged DNA or any other alteration in cell that can lead to abnormal cell. The mitigation of apoptosis is done by impairing the DNA damage sensing mechanism through production of abnormal p53 or suppressing its expression. AKT pathway is being upregulated transmitting antiapoptotic signals ensuring tumor survival. FAS is another receptor that facilitate the natural cell death. Tumors overexpress its natural decoy ligand to impair the FAS functioning. pTEN tumor suppressor is substantially downregulated. Tumors have acquired functionalities and pathways to ensure their survival by modulating the proaopototic proteins and pathways