Genetic And Molecular Basis Of Metastasis

Introduction

Metastasis is the process by which cells from the primary tumour spread to other parts of the body.¹ It is a very complex phenomenon that, despite great success in cancer research and treatment, remains one of the biggest challenges. From this view, understanding the genetics and molecular mechanisms of metastasis is very important for inhibiting its progression by targeted therapies. Identification of the genetic changes and mutations that favour metastatic spread also provides information potentially useful in identifying therapeutic targets and strategies for the prevention and/or treatment of metastatic disease. Determination of the molecular routes required for metastasis will also provide information regarding the mechanisms of tumour progression to identify factors involved in treatment resistance and disease recurrence.

Definition of metastasis

Metastasis is a multistep process in which cancer cells lose their adhesion to primary tumours and invade the neighbouring tissues and dissociate into blood vessels and lymphatic vessels for the spread into the distantly located organs. This is a multi-step process that involves local invasion, intravasation (the cancer cell passes into the blood or lymphatic vessels), survival in the circulatory system, extravasation (the cancer cell moves out of the blood or lymphatic vessels) at distant sites, and colonisation in new tissues.² 

Genetic factors of metastasis

Various genetic factors affect metastasis. Studies in the past years have shown that genetic understanding of the metastasis process was important for developing target therapies inhibiting this deadly progression. Also, the interaction of genetics and epigenetics with nutrition is probably the most exciting area wherein to study the relationship between genetic predisposition and environmental factors, like diet, in the development and progression of metastatic cancer.³ 

Genetic markers of metastasis

The last years have brought immense progress in the field of identifying genetic markers associated with cancer metastasis. It has been shown that particular genes and mutations have a great impact on increasing cancer cell migration from the primary tumour into distant organs. For example, mutations in the TP53, PTEN, and RB genes have been described in various types of cancer, such as breast and lung cancer, and are correlated with higher metastatic potential.^4,5  Also, some important genes responsible for cell adhesion, migration, and invasion are differentially expressed in a manner that favours the process. Some of these genetic markers include VCAM1, EREG, MMP1, Id1, IL11, CTGF, CXCR4, PTGS2, CXCL1 ST6GALNAC5, BRCA1, MYC, along with microRNAs and non-coding RNAs.⁶ 

Roles of oncogenes and tumour suppressor genes in metastasis

Oncogenes and tumour suppressor genes also contribute to important roles during the process of metastasis. Jointly, oncogenes can, if mutated, initiate cell proliferation and invasion-that is, cancer growth.⁷ Tumour suppressor genes, on the other hand, are inherited molecules that function to keep cell growth and cell division on a tight leash, thereby serving as protection against tumorigenesis – when a normal cell transforms into a cancer cell.⁸ Tumour cells proliferate and survive and the oncogenes enhance this proliferation and survival, which then invade the surrounding tissues and lymph nodes in the context of metastasis. Conversely, mutations in tumour suppressor genes inactivate their biological ability inhibiting cell growth and invasion and enhance this spread of cancer to distant organs.⁹ 

Molecular mechanisms of metastasis

Metastasis is at the centre of cancer progressions and under the control of molecular programs in both the tumour cells and host microenvironments. Genetic defects, including mutations in cancer-related genes, promote the invasive capability of cancer cells to invade through tissue barriers and spread throughout the body. Molecular mechanisms of metastasis include but are not limited to, the activation of stress response genes, post-transcriptional modulation of gene products, and invasiveness acquired by complex cellular processes like epithelial-mesenchymal transition.² 

Molecular markers of metastasis

Metastasis accounts for the majority of cancer deaths and remains one of the most difficult aspects of cancer biology to predict and clinically manage.¹⁰ Though conventional methods like lymph node status and histopathology, to name a few, are effective in their own right, they nevertheless remain within a narrow scope as far as the prediction of metastasis is concerned. Newer mechanisms developed under the considerations of mechanobiology offer new prospects to assess cancer cells for mechanical invasiveness with better chances of predicting metastasis.¹¹ 

Molecular markers associativity with epithelial-to-mesenchymal transition (EMT) have proved to be conclusive in predicting the metastatic potential in prostate cancer by analysing the EMT markers. Some of these identified molecular biomarkers include cytokeratin 8 (CK8) and mesenchymal vimentin (Vim).¹² 

Another research work found that the levels of some molecular biomarkers had a direct correlation with metastasis. These markers included carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC-Ag), cytokeratin-19 fragment (CYFRA 21-1), neuron-specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP), total prostate-specific antigen (TPSA) and carbohydrate antigen 199 (CA199).¹³ Because molecular markers of metastasis will be described, a biomarker panel of this nature applied in a clinical setting will enable much more targeted and potent interventional therapies that steer patient outcomes in the therapy of metastatic disorders.

Signalling pathways associated with metastasis

Several pathways exist to which metastasis can be attributed. There is one very important pathway, and that is, the EMT. It is an already known process by which cells lose epithelial cell-cell adhesion and then become highly migratory and invasive to invade surrounding tissues, thus forming metastasis.¹⁴ Modulation of this pathway relies on key transcription factors like Snail, Twist, and Zeb, which in turn, modulate the expression of gained or lost genes responsible for cell adhesion and migration.¹⁵ Moreover, cell proliferation, survival, and invasion are induced by the activation of various receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (HGFR) or c-Met and thus collectively favour the metastatic cascade.¹⁶  Also, the activation of multiple associated signalling pathways like the MAPK/ERK, PI3K/Akt, and Wnt/β-catenin controlling various vital cellular processes such as proliferation, survival, and motility add to the potential of tumour cells to metastasize.¹⁷ 

Summary

The tour regarding the genetics and molecular basis of metastasis has unveiled that pending behind cancer cell spreading is a very complex mechanism. Researchers have benefited a lot from surveilling the role of various genes, signalling pathways, as well as microenvironment factors, thereby understanding the complexity of metastasis.

With the effective role of key genes like TP53, PTEN, RB, BRCA1, MYC, along with microRNAs and non-coding RNAs involved in it, the genetic alterations which accelerate the process of metastatic progression are significantly known. 

In addition, crosstalk between tumour cells and host stromal cells as well as immune cells and extracellular matrix components are equally important in metastatic dissemination, equally important as individual cell genetic progression. 

Moreover, the deregulation of important molecular pathways related to cell adhesion, migration, or invasion can contribute to the entire process of metastasis. In the future, more studies are required to be conducted to properly understand the entire genetic and molecular alterations that occur towards metastasis and eventually prepare targeted therapy that can prevent or effectively cure metastatic cancer. 

The genetic and molecular mechanisms of metastasis will facilitate the development of targeted therapies that may successfully prevent or treat metastatic diseases.