Role of Nanotechnology in Cancer Therapy

By Priya Patel

The role of Nanotechnology in Cancer Therapy gives an overview of the innovative nanocarrier-based approaches for managing various cancers such as gastric, skin, lung, and prostate cancers. The book also explores the evolving targeting approaches specific to cancer and the immunotherapy-based nanomedicine approach. Several drug-delivery systems that reduce the overall toxicity of cytotoxic drugs and increase their effectiveness and selectivity are also discussed in this book.Key Features- Discusses the potential benefits and therapeutic applications of nanoparticles in cancer management
- Provides information about therapy in a range of cancers- Discusses recent developments in cancer nanomedicine including targeted therapy, immunotherapy nanoparticles and dual drug delivery- Includes safety and toxicity considerations- Provides references for advanced readers
This book will inform a broad range of readers including undergraduate and postgraduate students, oncologists, pharmacists, and researchers involved in nanomedicine and nano-drug delivery about current advancements in cancer nanomedicine.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Feb 16, 2000
• ISBN: 9789815079999

Book preview

Cancer Pathophysiology

Devang B. Sheth¹, *, Chirag A. Patel¹, Sandip B. Patel¹

¹ Department of Pharmacology, L.M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India

Abstract

Cancer prevalence across the globe has increased substantially in the last two decades despite significant progress in inpatient care. Cancer, a multifactorial disease, evolved several theories to establish pathophysiological conditions. Uncontrolled proliferation, dedifferentiation and metastasis mainly describe the cancer progression, which must be characterized by cellular and molecular changes. Understanding these processes helps devise the strategy for effectively delivering the drugs to the target sites. The present review described the essential features of cancer pathophysiology and challenges to achieving drug concentration in the targeted area.

Keywords: Dedifferentiation, Metastasis, Nanotechnology, Uncontrolled Proliferation.

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* Corresponding author Devang B. Sheth: Department of Pharmacology, L M College of Pharmacy, Navrangpura, Ahmedabad-380009, Gujarat, India; Tel: [phone]; E-mail: [e-mail]

INTRODUCTION

Cancer is a heterogeneous group of diseases that evolved from a complex multistage process resulting from genetic and epigenetic abnormalities, resulting in dysregulated gene expression [1-3]. All conditions categorised under 'Cancer' share common phenotypic characteristics of uncontrollable cell growth and proliferation. 'Cancer' is derived from the Greek word 'Karkinos,' meaning crab. The etymology correlates with the appearance of finger-like spreading projections from a tumor [4, 5]. Globally, cancer is the second leading cause of mortality below 70 years. Amongst the ranking of premature mortality across the globe, cancer stands 1st across 57 countries, 2nd across 55 countries and 3rd-4th across 23 countries [6]. The world has observed an alarming increase of nearly 100% in new cancer cases from 10 million in 2000 to 19.3 million in 2020. This trend continues to be kept in the last few decades in developed and developing countries with advancements in socioeconomic status and an increase in the average lifespan of human beings. As per Global Cancer Statistics, nearly 10 million deaths due to cancer were reported in 2020 against 6 million deaths in 2000 [6, 7].

Etiopathogenesis

The transformation of a normal cell into a tumor cell is primarily due to one or more DNA alterations that dysregulate gene structure and expression [8, 9]. These alterations may either be inherited or acquired/provoked by exposure to a carcinogen(s).

Aetiology

Alteration(s) of DNA (i.e., mutation) can be provoked by primary carcinogen, secondary carcinogen, co-carcinogen and promoter. Primary carcinogens, such as physical, biological and chemical agents, produce mutagenesis resulting in carcinogenesis. Secondary carcinogen (commonly referred to as pro-carcinogen) mediates the process of carcinogenesis after being converted into active metabolites. Co-carcinogen increases the process of carcinogenesis when administered with a carcinogen, while (tumor) promoter does the same when administered after a carcinogen. Both co-carcinogen and promoter do not possess carcinogenic potential when given alone (Fig. 1). However, it is complicated to determine the etiology of cancer in clinical practice.

Fig. (1))

Process of Carcinogenesis.

Examples of physical carcinogen include ionizing radiation (e.g. γ-rays, X-rays) and non-ionizing radiation (e.g. UV-rays) [10-13]. Squamous cell carcinoma resulting from sun-exposed areas and Kangari cancer due to the use of traditional fire-pot in some areas of Kashmir are examples of cancer produced by physical carcinogens [14-16].

Biological agents such as bacteria, fungus and more commonly viruses can cause direct DNA damage, produce carcinogens or introduce oncogenes in the host cell. Cervical, penile, anal, oral and pharyngeal cancer caused by Human Papillomavirus (HPV); Burkitt's Lymphoma caused by Epstein-Barr Virus (EBV) and Kaposi's Sarcoma caused by Human Herpes Virus 8 (especially in patients of HIV infection) are some examples of biological carcinogen. Growth of Aspergillus flavus resulting in the release of aflatoxin can lead to hepatocellular carcinoma. Infection with Helicobacter pylori is a recognized etiopathological factor for incidences of gastric adenocarcinoma.

Chemical carcinogens can be classified into genotoxic and non-genotoxic carcinogens based on their biological activity [17, 18]. Genotoxic carcinogens cause mutation by covalently modifying the nitrogenous bases of DNA (particularly guanine) [19, 20]. O6 and N7 positions of guanine base can readily and covalently associate with reactive metabolites of chemical carcinogens. Substitutions at N7 positions may get repaired quickly, but O6 positions are not. Thus, permanent mutagenic effects are usually due to substitutions at O6 positions [20, 21]. Chemicals present in tobacco like polycyclic aromatic hydrocarbons, nicotine, coal tar and nitrosamine NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) when consumed through chewing, smoking or sniffing, greatly increases the possibility of such substitutions [22]. Tobacco products are the leading cause of lung and oropharyngeal cancers. Association of asbestos in lung cancer; heavy metals like arsenic in liver, lung and skin cancer and benzene in leukemia is well documented [20, 21, 23-29]. Non-genotoxic carcinogens mediate their action by modifying epigenetic mechanisms [17, 18].

Pathogenesis

Damage to the genomic structure of cells or altered phenotypic expression of genes is a common feature for all neoplasms. Despite the high fidelity of DNA replication, it is a fact that spontaneous mutation in eukaryotic cells occurs at the rate of 10-10-10-12 errors per base pair per generation [30]. Although low, it is an inevitable and inherent error rate in DNA replication. Thus, all multicellular organisms face the near-certainty of developing a neoplasm if their survival tenure is long enough [31]. Many non-lethal and inconsequential mutations in a minor subset of the coding and non-coding regions of the genome can give rise to carcinogenesis [32]. Oncogene is a mutated gene that can cause cancer by accelerating proliferation through dysregulating the cell cycle or inhibiting apoptosis [33-35]. Major 2 categories of genetic change that lead to cancer include:

(a) Activation of proto-oncogenes to oncogenes

(b) Inactivation of tumor suppressor gene

Such changes are resultant of chromosomal aberrations (e.g., chromosomal translocation, deletion, aneuploidy) and intragenic/point mutations (e.g., substitution mutation, frameshift mutation) [35, 36].

The Philadelphia chromosome produced by reciprocal translocation leading to chronic myelogenous leukemia (CML) and many other types of leukemia is a classic example [37, 38]. Expression of the Philadelphia chromosome produces a fusion protein consisting of BCR and ABL. This mutant protein BCR-ABL with kinase activity leads to dysregulation of cell cycle regulation, stimulating uncontrolled cell division [37-39].

Inactivation of tumor suppressor genes like BRCA (Breast Cancer), APC (Adenomatous Polyposis Coli) and RB (Retinoblastoma) by deletion or truncating mutations is observed in various types of cancer [40]. Gene expression of BRCA1 and BRCA2 leads to tumor suppressor gene protein production. Thus, mutation involving both or any of these gene(s) increase(s) the risk of breast cancer (in both females and males) and ovarian cancer [41-43]. Such mutation may result in consequences leading to interference with Lyonization (a process of X-Chromosome inactivation) [44]. Pathogenic variants of these genes are also implicated in increased prostate cancer, gastric cancer, colon cancer, pancreatic cancer and melanoma [42, 45]. APC-mutant phenotypes are associated with colon, gastric and pancreatic cancer [46-48]. The G1/S checkpoint of the cell cycle is negatively controlled by RB protein. Deletion of RB1 gene prevents arrest of the cell cycle, leading to malignant retinoblastoma [49, 50]. Cervical cancer, mesothelioma, and AIDS-related Burkitt's lymphoma are some examples of RB protein's functional inactivation [51].

Genetic alteration leading to loss or gain of the whole chromosome is referred to as aneuploidy. Chromosomal instability, a major event that gives rise to aneuploidy, can promote carcinogenesis by increasing genetic heterogeneity [52]. Aneuploidy is observed more frequently in the tumor development process than other types of mutations [53].

Substitution mutation in the KRAS (Kristen rat sarcoma virus) gene of the RAS family contributes to the development and progression of colon cancer [54]. The RAS mutants exhibit an impaired ability to hydrolyze GTP either intrinsically or in response to GTPase-activating proteins. This further modulates proliferative-pathway signalling via Raf/mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K), leading to uncontrolled proliferation [55-57]. Another example is the TP53 gene, where the substitution of a single nucleotide can lead to the early onset of several types of cancers [58].

Regulation of gene expression through epigenetic mechanisms, viz. histone acetylation, DNA methylation and microRNA expression, can also be pivotal in neoplastic transformation. Epigenetic mechanisms can reduce, enhance or completely silence genetic expression [59]. Epigenetic factors (viz. hormone, co-carcinogen, a tumor promoter, etc.) do not themselves produce mutation but enhance the likelihood that genetic mutation(s) will eventually result in cancer. It is important to note that epigenetic changes are reversible and inherited [60, 61].

CHARACTERISTICS OF CANCER CELLS

Concept of Heterogeneity

Cancers tend to grow increasingly diverse as the disease progresses. Due to this heterogeneity, the bulk tumor may contain a heterogeneous collection of cells with discrete molecular fingerprints and varying levels of treatment sensitivity. This heterogeneity could lead to a non-uniform distribution of genetically different tumor-cell subpopulations across and within disease sites (spatial heterogeneity), as well as temporal fluctuations in cancer cell genomic makeup (temporal heterogeneity) [62].

Uncontrolled Proliferation

Uncontrolled proliferation is considered to be an essential mechanism of cancer cells. It results due to the loss of tightly regulated mechanisms prevailing in the growth of normal tissues. Genesis of cancer involves multiple processes which make pathological changes in tissue architecture followed by pre-neoplastic nodule formation that lead to the appearance of cancer. While growth factors and hormones drive the growth and survival of normal cells in part, mutations and epigenetic changes mediated modifications in signalling pathways make cells resistant and independent of these pathways. Alterations in the cellular system such as epithelial to mesenchymal transition (EMT), autophagy, cancer stem cells, cell cycle regulators, altered cell metabolism, hormone signalling and angiogenesis provide a cell autonomy of growth resulting in uncontrolled proliferation [63].

EMT and Tumor Proliferation

EMT is linked to the Snail family of transcription factors (Snail1/Snail and Snail2/Slug). EMT is believed to suppress the expression of E-cadherin, which is normally involved in the regulation of cell-cell interactions, providing polarity cues and preventing the spreading of tumors [64]. Cancer may progress if tightly regulated Snail-associated EMT is lost, leading to the loss of the regulatory mechanism of contact inhibition. Snail overexpression protects cells from death mediated by a lack of survival factors or apoptotic triggers. Snail2/Slug may also influence cellular response to genotoxic stress, resulting in increased DNA damage, leading to cancer development. Enhanced Snail1/2 levels result in higher DNA damage protection and increased resistance to chemotherapeutic and radiation therapy [65].

Autophagy

Basal autophagy maintains cellular homeostasis by eliminating protein aggregates and damaged organelles in normal cells [66]. In contrast, autophagy induced by starvation can cause the recycling of amino acids and energy, which extends the longevity of cells. Autophagy increases in cancer cells in response to stressors such as deregulated signalling-mediated proliferation, increased glycolysis, and hypoxia and keeps tumor cells in a dormant condition under the presence of survival factors in microenvironments [67]. However, depending on the type of tumor, autophagy can increase tumor cell survival or cell death; therefore, the consequences of induced autophagy are not fully known. Thus, therapeutic manipulations can promote survival or death [68].

Cancer Stem Cells

The features of stem cells (SCs) and cancer stem cells (CSCs) are similar in terms of stemness, quiescence, self-renewal, the ability to produce differentiated progeny, apoptosis resistance, and chemoresistance. The abnormal regulation of these activities in CSCs differentiates them from mature SCs, resulting in altered cell characteristics and uncontrolled cell proliferation [69].

Tumor mass containing a small fraction of CSCs is proven to maintain sustained malignant proliferation and differentiated progeny cells of CSCs. Adult SCs produce differentiated daughter cells but reveal the limited cell division capacity of progenitor cells. Whereas CSCs divide symmetrically into progenitor cells, allowing them to replicate infinitely, which explains the relapse of the tumor even after the destruction of mature tumor cells by initial therapy, treatment-resistant CSCs remain active and proliferate [70]. The treatment also requires targeting CSCs efficiently to achieve complete remission.

Dysregulation of stem cell pathways could cause progenitor cells to adopt stem cell phenotype. It's still unclear if cancer stem cells are dedifferentiated progenitor cells with limitless proliferating capacity or stem cells that have escaped homeostasis. Dedifferentiation may have a role in developing some malignancies, according to studies. In vitro breast cancer cell lines, cell sorting has shown that stem-like cells may form de novo from non-stem-like cancer cells [71]. It has been demonstrated that leukemic stem cells can be created from committed progenitor cells that acquire stem cell-like activity in the hematological system. AML is considered a progenitor illness, in which a progenitor acquires aberrant self-renewal capacity and dedifferentiates into a stem cell-like condition [72].

Cell Cycle Transducers

The cell cycle is a crucial process that governs genome duplication and cell division. Briefly, the cycle is divided into four phases: G1 (Gap 1), S (DNA synthesis), G2 (Gap 2), and M (Mitosis), with various checkpoints to ensure preserved replication and segregation into daughter cells. These checkpoints protect against genomic instability, promoting or accelerating tumor growth. Cyclins and cyclin-dependent kinases (CDKs) are the cell cycle's orchestrators, and their expression and activity change as the cell cycle progresses [73].

The formation of cyclin-CDK complexes allows phosphorylation of targets like RB to influence cell cycle progression. Cyclin-dependent kinase inhibitors (CDKIs) control the cyclin-CDK complexes themselves, including the INK4s: p16INK4A/CDKN2A, p15INK4B/CDKN2B, p18INK4C/CDKN2C, and p19I- NK4D/CDKN2D; and the CDK-interacting protein/kinase inhibitory proteins (CIP/KIPs): p21CIP1/WAF1/ CDKN1A, p27KIP1/CDKN1B, and p57KIP2/ CDKN1C. Further, E3 ubiquitin regulates the production of mitotic proteins like the Skp1– Cul1–F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C) to govern cell cycle transitions [74].

Mitogens normally regulate the progression of cells through the G1 phase of the cell cycle. Uncontrolled proliferation is often accompanied by the loss of control laid down by mitogens mediated by cyclins and CDKs. Production of cyclin D1 promotes the partial inactivation of RB and the formation of cyclins E and A through E2F mediated transcription factors essential for the G1/S transition and DNA replication, which intensify inactivation of RB, leading to bypassing the G1/S restriction point. Cyclin A-CDK2 drives the transition from S/G2 at the end of the S phase, and cyclin A's subsequent activation of CDK1 causes cells to begin mitosis. CDK1 binds to cyclin B and pushes cells through mitosis once cyclin A is deactivated [75]. Monitoring the DNA integrity through the cell cycle checkpoint is essential for the G1/S and G2/M transition. In DNA damage, cell cycle progression is not favoured under the influence of CDKs inhibition which makes all efforts to correct the error. But if an error is not resolved, cells undergo cell death or senescence.

Cancer cells phenotype, which outweighs many regulators of cell cycle attained through genetic and epigenetic alterations, promotes uncontrolled proliferation. Expressions of cyclins and CDKs at different cell cycle stages are routinely elevated in numerous cancers. Therefore, cyclins and CDKs are considered the potential targets of cancer treatment. However, several CDK inhibitors failed in clinical trials for unknown reasons.

Cellular Metabolism

Proliferating cancer cells require increased ATP production, macromolecule manufacturing, and abnormal cellular redox status maintenance. The tumor suppressor p53, for example, activates glycolytic enzymes and the pentose phosphate pathway, which supply macromolecular synthesis substrates [76]. Furthermore, the M2 isoform of pyruvate kinase (PKM2), which converts phosphoenolpyruvate to pyruvate, inhibits glycolysis, supplying macromolecular synthesis precursors [77].

Hepatic steatosis associated with non-alcoholic fatty liver disease (NAFLD) is associated with inflammation, which may progress to fibrosis. The resultant effect, which alters cellular metabolism, is involved in the Etiopathogenesis of cancer. It is also imperative that patients having liver fibrosis are at risk of developing hepatocellular cancer (HCC). Alterations in methionine metabolism play an important role in the molecular basis of NAFLD-related HCC [78].

Hormone Signalling

Hormonal dysregulation is a known epigenetic factor to cause cancer progression. Hormone-related cancer constitutes almost 30% of all cancer cases, mainly cancers of reproductive organs such as breast, ovary, endometrium, testis and prostate. Steroid hormones induced proliferation of normal cells makes them more vulnerable to DNA damage and oncogenic mutation [79]. Numerous interconnected pathways produce abnormal tumor growth [80]. IGFR-1/IGF-1 and increased EGFR/ErbB-2, combined with downstream Akt and Janus kinase (JAK)/STAT and MAPK signalling, are also involved in androgen-independent prostate cancer. These pathways activate the androgen receptor, which travels to the nucleus and changes host gene expression, promoting cell survival and proliferation [81].

Telomerase Expression

Telomerase activity, seen in nearly 90% of all human malignancies, is likely to be the source of uncontrolled tumor cell multiplication [82]. Overexpression of TERT, which encodes the reverse transcriptase subunit of telomerase, resulted in the uncontrolled proliferation of many types of cancers without affecting the length of telomeres. Oncogenic transcription factors Myc, nuclear factor κ-light chain-enhancer of activated B cells (NF-κB), and β-catenin, on the other hand, reactivate TERT transcription in cancer cells. As a result of oncogene activation, telomerase expression increases, overcoming replicative senescence [62].

Angiogenesis

Tumor development relies on a steady supply of oxygen and nutrients from the blood vessels. However, in fast-developing tumors, the supply from the existing vasculature is frequently insufficient, resulting in intratumoral hypoxia [83]. Up-regulation of hypoxia-inducible factors, HIF-1 and HIF-2, under low oxygen tension, low glucose levels, and acidic extracellular pH leads to activation of genes that mediate proliferation, angiogenesis, intermediate metabolism (glycolysis) and pH regulation. Proliferative signals received through HIFs activation trigger growth factors such as TGF- β, IGF-2, IL-6, IL-8 and growth factor receptors EGFR [63]. The expression of growth factors, in turn, stimulates tumor angiogenesis by causing endothelial cells (ECs) to proliferate and survive, resulting in a plethora of deformed and malfunctioning neo-vessels inside the tumor.

De-differentiation and Loss of Function

Many studies have suggested that the origin of cancer cells is somatic cells [84, 85]. However, the progenitor cells/ stem cells are more likely to transform into cancer cells. Some reports also suggested cancer development from mature cells [86, 87]. Dedifferentiated tumors are considered to be involved in cancer initiation and progression. Dedifferentiation is the process where somatic cells acquire unlimited proliferation and self-renewing activities, as observed with stem cells. Dedifferentiation of non-stem cells in the intestine, resulting in the acquisition of tumor-initiating capacity with stem cell properties, is induced by Wnt signalling along with the elevated levels of NF-kB [87]. Moreover, the origin of tumor cells in glioma is attributed to dedifferentiation into the differentiated lineage [88].

Metastasis

In the process of metastasis, cancer cells detach from the original (primary) tumor, move via the blood or lymph system, and develop a new tumor in other organs or tissues of the body [89]. Cancer metastasis is the primary cause of cancer death and morbidity [90]. Malignant tumors are known for their tendency to metastasize [91]. It is a complex sequence of cell-biological events known as the invasion–metastasis cascade, which may overlap (Fig. 2) [92].

The cascade involves:

1. Separating tumor cells, invasion and cell migration;

2. Intravasation into the vasculature or lymphatic system;

3. Circulation survival;

4. Extravasation from the vasculature to secondary tissue; and

5. Metastatic colonization (Colonization at secondary tumor sites).

Fig. (2))

Invasion–metastasis cascade. The cascade involves 1. The separation of tumor cells from their neighbouring cells in the primary tumor, Migration within the stroma (Cross-talk with the stroma cells, orientation within the stroma, Immune cell attack and EMT), invasion through the basement membrane (BM) and ECM surrounding the tumor, invasion of the BM supporting the endothelium of local blood and lymphatic vessels; 2. Entry or intravasation of the metastatic cells into the blood vessels; 3. Survival within the circulation, adhesion of the circulating metastatic cells to the endothelium of capillaries of the target organ site; 4. Extravasation; invasion of the cells through the endothelial cell layer and the surrounding BM; and 5. Metastatic colonization, expansion of secondary tumors at the target organ site. Dotted rectangle callout (Black) includes markers/genes involved in the signalling pathway. EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition.

Separation of Tumor Cell, Invasion and Cell Migration

The separation and migration of cells from the primary tumor mimic the epithelial-mesenchymal transition (EMT), a process in which polarised epithelial cells acquire the migratory and invasive characteristics of mesenchymal cells [93]. During EMT, polarised epithelial cells undergo biochemical changes that cause them to adopt a mesenchymal phenotype characterized by a loss of cell polarity, decreased cell-cell adhesiveness and increased invasive capability [94-96]. The loss of adherens junctions decreased epithelial-specific markers like cytokeratins and E-cadherin, and increased mesenchymal markers like fibronectin, N-cadherin, and vimentin characterized the EMT [97-102].

Cancer cell invasion occurs when a phenotypic mesenchymal cell breaches its basement membrane and invades the surrounding stroma. Depending on the nature of the EMT program, the tumor cell invasion is frequently conceptualized as a process involving single-cell invasion, trailblazer-type collective invasion, or opportunistic collective invasion [103]. Tumor cell-extrinsic alterations in the microenvironment attract tumor cells into the local tissue, and activation of signalling pathways within tumor cells at the genetic and protein level enables cell motility and extracellular matrix (ECM) degradation, resulting in an invasion [104]. To promote invasion, a signal like growth factors and cytokines can attract tumor cells via chemotaxis [105]. Tumor cells can also migrate through gaps in the ECM using force-dependent cytoplasmic blebbing independent of protease activity. The local invasion is mediated through different signalling pathways that enhance the cytoskeletal dynamics [105-112].

Intravasation into the Vasculature or Lymphatic System

Intravasation into the vasculature's lumen or lymphatic system can be active or passive, depending on the tumor type, microenvironment and vasculature [112]. According to the three-dimensional microfluidic model, the endothelium operates as a barrier to tumor cell intravasation and is controlled by components present in the tumor microenvironment [113]. Wong et al. also reported that tumor cells at the blood vessel's periphery break the endothelium and enter circulation via a mitosis-mediated process [114]. Furthermore, during intravasation, the architectural restrictions of tissue put mechanical stresses on invading tumor cells [119]. Tumor cells become circulating tumor cells (CTCs) as they reach the vasculature and can be used as a biomarker for all solid tumors [115].

Survival in the Circulation

Most intravasation cancer cells have difficulty making their way through the circulatory system. Interactions between CTCs and the microenvironmental components of circulation determine CTC survival and capacity to extravasate at distant places [116]. Most CTCs travel in single, while others travel in clusters [117]. Circulating clusters have a considerably higher chance of becoming metastases. Clusters include CTCs, stromal cells and immunological components from the initial cancer milieu, all of which contribute to the cluster's heterogeneity and increase its longevity [118-121]. Neutrophils help CTCs survive by assisting in cluster formation and suppressing leukocyte activation [121]. Furthermore, CTC-platelet interactions create platelet covering layers over CTCs, which prevents the immune system from detecting circulating tumor cells and provides the stability needed to withstand the physical demands of circulation [122-124].

Extravasation from the Vasculature to Secondary Tissue

The capacity of circulating tumor cells to attach and extravasate via endothelial cells is critical in metastasis [125]. CTCs become entrapped when they pass through small capillaries. As a result, the microvessels rupture, or the tumor cell is forced to extravagate. In organs with highly permeable sinusoidal vessels, such as the liver and bone, CTCs have a high rate of metastasis [126]. Extravasating cells in other organs encounter tight barriers and the basal lamina, necessitating molecular and genetic regulation to penetrate [127].

Metastatic Colonization

The final biological activities required for cancer cells to produce a clinically meaningful metastasis in a secondary cancer location are metastatic colonization (s). Circulating tumor cells that flow out from the vasculature at the secondary tumor site face unfavourable environmental conditions that make endurance challenge. While hundreds of cancer cells can enter the bloodstream, most circulating tumor cells fail to initiate metastases within a secondary organ [128]. Various tumor-derived proteins and bone marrow-derived cells indicate the establishment of pre-metastatic niches, where tumor cells infiltrate and produce a secondary tumor [128, 129]. Furthermore, effective metastatic colonization necessitates cancer cell–host cell interactions and establishing a vascular network.

CURRENT CHALLENGES AND OPPORTUNITIES IN CANCER TREATMENT

Despite the advances in oncology research and chemotherapy development, cancer remains one of the most serious health challenges worldwide [130]. The current recommended conventional cancer treatment options include surgical removal of tumors, radiation, and chemotherapy [130]. Hormone therapy, anti-angiogenesis therapy, stem cell transplant, and immunotherapy based on dendritic cells (DC) are modern treatments.

Significant challenges associated with current cancer treatment are targeting cancer stem cells (CSCs), lack of cancer epigenetic profiling and specificity of existing epi-drugs, tumor heterogeneity, tumor microenvironment, drug resistance, limitations of conventional chemotherapeutic agents (non-specific targeting and poor pharmacokinetic characteristics pose different challenges of systemic toxicities) and the metastatic nature of cancer [131-133].

Thus, the intricacies of tumor Etiopathogenesis, combined with the challenges associated with current cancer therapy, necessitate new solutions, particularly novel therapies that can address the challenges mentioned above. Nanomedicine, oncolytic virotherapy, personalized vaccines, microbiome treatments, thermal ablation of tumors, antisense-RNAi techniques, and newly proposed multi-omic approaches (genomic, epigenomic, transcriptomic, epi-transcriptomic, and proteomic networks) are among the novel treatment systems used to treat the malignancy and overcome the limitation of conventional therapies. Nanomedicine emerges as an appealing approach to design and develop tailor-made medicine with improved efficacy and safety for the effective management of cancer.

Nanomedicine

Nanomedicine has emerged as a viable strategy for targeting chemotherapeutics to tumor tissues by exploiting the enhanced permeability and retention effect (EPR) produced by leaky tumor vasculature and insufficient lymphatic drainage [134-138]. Functional moieties (i.e., targeting ligands) can be conjugated to the surfaces of nanoparticles due to their unique physicochemical features, improving targeted delivery to tumor areas and reducing multidrug resistance [139]. This targeted drug delivery at the tumor site improves therapeutic outcomes and reduces the unwanted adverse effects of systemic delivery [140]. Furthermore, the capacity to control the size, composition and functionality of a wide range of nanoparticle platforms (organic, inorganic, and hybrid) has opened the door to developing cancer nanomedicine delivery systems [140]. Liposomes, micelles, gold nanoparticles, iron oxide nanoparticles, silica nanoparticles, carbon-based nanostructures, quantum dots, and hybrid nanomaterials are examples of passively targeted delivery systems. At the same time, active targeting includes silica, gold, liposomes, micelles, iron oxide, graphene, gadolinium, polymer nanocarrier, nanoemulsions, quantum dots, and hybrid nanomaterials [139].

Many nanomedicines have demonstrated acceptable clinical performance and have been approved by various regulatory agencies across the globe. However, it is imperative to overcome the potential problems of nanomedicines concerning non-specific macrophage uptake, thick tumor stroma, high interstitial fluid pressure, slow nanoparticle diffusion, etc., to achieve desired benefits in cancer treatment.

CONCLUSION

Currently, we have witnessed an enormous improvement in our understanding of the pathophysiological aspects of cancer concerning uncontrolled proliferation, dedifferentiation, invasiveness and metastasis. Continuous exploration of interactions between the nanomedicine approaches and tumor microenvironments will open new avenues in the delivery of drug molecules to particular target sites and an acceptable safety profile.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENT

Declared none.

REFERENCES