Neha Merchant

Matrix metalloproteinases: Their functional role in lung cancer

Lung malignancy is the foremost cause of cancer-related deaths globally and is frequently related to long-term tobacco smoking. Recent studies reveal that the expression of matrix metalloproteinases (MMPs) is extremely high in lung tumors compared with non-malignant lung tissue. MMPs are zinc-dependent proteases and are involved in the degradation of extracellular matrix (ECM). Several investigations have shown that MMPs manipulate the activity of non-ECM molecules, including cytokines, growth factors and receptors that control the tumor microenvironment. In this review, we have summarized and critically reviewed the published works on the role of MMPs in non-small-cell lung cancer. We have also explored the structure of MMPs, their various types and roles in lung cancer metastasis including invasion, migration and angiogenesis.

Role of hypoxia-inducible factors (HIF) in the maintenance of stemness and malignancy of colorectal cancer

Hypoxia is a condition of insufficient tissue oxygenation, which is observed during normal development as well as tumorigenesis and its response at the cellular level is primarily mediated through hypoxia inducible factors (HIFs). HIFs have a significant role in the maintenance of stemness in both stem cells as well as in cancer stem cells (CSC) by acting as transcription factors. The CSCs are proposed to be the driving force of colon tumorigenesis and malignancy. These HIFs play a significant role in a wide range of diseases including colon cancer. HIFs signaling functions with stemness, and maintaining Wnt/β-catenin signaling pathways. Due to HIFs functional significance in stemness maintenance in malignancy, targeting HIFs might provide a new approach for development of new therapy for colon cancer. In this review, we will be briefing on the colon and its stem cells, various molecular signaling pathways involved in stemness preservation, and the role hypoxia and its HIFs in the maintenance of stemness in colon stem cells and colon cancer stem cells.

Adiponectin: Its role in obesity-associated colon and prostate cancers

Adipose tissue synthesizes many proteins and hormones collectively called adipokines, which are linked to a number of diseases, including cancer. Low levels of adiponectin are reported to be a risk factor for obesity-related cancers including colorectal and prostate cancers. Accordingly, obesity/lifestyle-related diseases, including certain cancers, may be treated by developing drugs that act specifically on adiponectin levels in circulation. Adiponectin may also serve as a clinical biomarker in obesity-related diseases. Adiponectin-based therapies are known to inhibit cancer advancement and thus may provide a therapeutic approach to delay cancer progression. Better understanding of the function of adiponectin is of great significance in the fight against cancer. This timely review is concentrated on the role of adiponectin and the impact of obesity on the development of cancers, especially colorectal and prostate cancers.

Nanomaterials: Diagnosis and Therapeutic Properties

Therapeutic strategies toward the treatment of gastrointestinal (GI) malignancies frequently involve the administration of increased dosage of chemotherapeutic drugs, often resulting in nonspecific toxicities. Although conventional radio- and chemotherapy have been the gold standard of cancer therapy for decades, these approaches are not optimal and can lead to resistance to these and other therapies. Effectiveness of GI malignancy therapies depends on fine-tuning of eradication of cancer cells with minimal or ideally no toxic effect on normal cells. Nanomaterials (NMs) offer a solution for targeted killing of cancerous cells without causing damage to the healthy host cells. NMs are appealing drug carriers based on their high tissue permeability, high colloidal stability, small size in the nanometer range, high surface-to-volume ratio (large amount of drug can be loaded), aqueous solubility, ease of characterization, and surface modification. The enhanced permeability and retention (EPR) effect of NMs permit accumulation at the tumor site. Apart from the passive accumulation of nanoparticles at tumor sites, NMs actively delivered the drug at tumor sites by loading with various growth factor receptors, peptides, shRNA, and small molecules. In this chapter, we will discuss the impact of NMs on tyrosine kinases associated with growth and metastasis of selected GI malignancies.

EGFR and FGFR in Growth and Metastasis of Colorectal Cancer

Colorectal cancer (CRC) is the most important cause of tumor-related fatalities around the world, and its distant metastasis is responsible for 40% of mortalities in the USA as well as around the world. CRC is not a single disease; it is rather an assortment of multiple cancers. Metastatic CRC develops from the relapse period after the therapy, where the cancer cells develop resistance. Due to the heterogeneous biology, clear descriptive study at molecular level about the mechanisms, which takes place during CRC invasion and proliferation, is necessary. These studies can help understand the factors affecting the increased risk of CRC progression and help deduce novel therapeutic strategies. This chapter includes the mechanism of EGFR and FGFR in CRC, which are common targets for therapy since they induce cell proliferation and cell division and inhibit apoptosis. Their overexpression in CRC is associated with metastasis including invasion and angiogenesis.

5-Lipoxygenase: Its involvement in gastrointestinal malignancies

Lipoxygenases (LOXs) are dioxygenases that catalyze the peroxidation of linoleic acid (LA) or arachidonic acid (AA), in the presence of molecular oxygen. The existence of inflammatory component in the tumor microenvironment intimately links the LOXs to gastrointestinal (GI) cancer progression. Amongst the six-different human LOX-isoforms, 5-LOX is the most vital enzyme for leukotriene (LT) biosynthesis, which is the main inflammation intermediaries. As recent investigations have shown the association of 5-LOX with tumor metastasis, there has also been significant progress in discovering the function of 5-LOX pathway in GI cancer. Studies on GI cancer cells using the pharmacological drugs targeting 5-LOX pathway have shown antiproliferative and proapoptotic effects. Pharmacogenetic discoveries in other diseases have revealed strong heritable basis for the leukotriene pathway, which helps in exploring the mechanistic source of genetic alteration within the leukotriene pathway and offer insights into GI cancer pathogenesis and future prospects for treatment and prevention. This review recapitulates the current research status of 5-LOX activity in GI malignancies.

Targeting autophagy in gastrointestinal malignancy by using nanomaterials as drug delivery systems

Autophagy is a conserved catabolic process involving large protein degradation by a ubiquitous autophagosomic signaling pathway, which is essential for cellular homeostasis. It is triggered by environmental factors such as stress, lack of nutrients, inflammation, and eliminating intracellular pathogens. Although the mechanisms underlying autophagy are still unclear, increasing evidence illuminates the magnitude of autophagy in a wide range of physiological processes and human diseases. Simultaneously, research community has focused on the triggering of autophagy by the internalization of engineered nanomaterials, which indicates a new line of revolution in cancer cure. However, most studies on nanoparticle-induced autophagy focus on brain, breast, and cervical cancers; limited reports are available on gastrointestinal (GI) cancers. Therefore, the aim of this mini review is to discuss in detail the role of autophagy in GI malignancy and the status of research on nanoparticle-induced autophagy.

Role of Hypoxia-Inducible Factor (HIF) in Liver Cancer

Liver cancer is one of the major causes of cancer-related deaths in the United States, accounting for 4.5% of the total estimated cancer deaths in 2016 and standing as the second leading cause of cancer-related deaths in men worldwide in 2012. There are two major types of primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The most common type of primary liver cancer is HCC, which begins in hepatocytes and accounts for approximately 75% of all liver cancers. Hypoxia, a condition of oxygen deprivation in the tissue, is a common feature of the cancer microenvironment due to increased cell proliferation and limited blood supply. Hypoxia-inducible factor-1 (HIF-1) was the first transcription factor discovered to regulate a wide range of target genes involved in many cellular processes in response to low oxygen levels. HIF-1 is a heterodimeric protein complex composed of two different subunits, α and β. During a condition of hypoxia, HIF-1 heterodimer activates target genes that contain a hypoxia response element (HRE) in the promoter region. The overexpression of HIF-1 is frequently observed in many human solid tumors, including liver cancer, and is associated with tumor development, poor prognosis, and resistance to chemotherapy, suggesting that HIF-1 is a new therapeutic target in liver cancer treatment. In this chapter, we define the molecular mechanism that controls HIF-1 and how it maintains a variation of biological processes in hypoxic environments.

Role of STAT3 in Liver Cancer

Hepatocellular carcinoma (HCC) is a malignant cancer that shows heterogeneous etiology and the third leading of cancer-related deaths in the world. In spite of its severity, there is only one systemic chemotherapy drug known as sorafenib showing a valuable effect on a small number of HCC patients. Signal transducers and activators of transcription (STATs), a family of transcription factors, consist of seven members in mammalian cells: STATs 1, 2, 3, 4, 5a, 5b, and 6. STAT transcription factors have a characteristic Src homology 2 (SH2) domain whose function is indispensable to the activation of STAT proteins triggered by Janus kinase (JAK) signaling. Among the STAT transcription factor family, STAT3 performs a vital function in advancement and tumorigenesis because it participates in replicating various proteins that are responsible for angiogenesis, proliferation, invasion, metastasis, and apoptosis. Although the activation of STAT3 is usually transient in normal cells, cancer cells show a positive feed-forward loop that results in the persistent activation of STAT3. The expression and activity of STAT3 are increased in a wide range of malignancies. Although several studies have reported the oncogenic functions, the antitumor effects of STAT3 should be considered carefully in the development of therapeutic methods that target STAT3 signaling. We believe that STAT3 signaling will be a promising target of treatment for HCC patients who need further research of adverse effects or personalized treatment via the modulation of STAT3 signaling.

Genistein and Its Role in Regulation of AP-1 in Colorectal Cancer

Colorectal cancer (CRC) is a prominent source of cancer-related deaths across the world. AP-1 is involved in CRC growth and metastasis. AP-1 is a transcription factor that regulates many oncogenic transduction pathways. In the current chapter, we discuss the importance of AP-1 on CRC growth and metastasis. Additionally, we discuss the mechanism of genistein, a tyrosine kinase inhibitor, and its effect on CRC treatment.