Overview

Originating from a Greek word that means translocation and settling to another area, metastasis remains to this day an advanced stage of cancer that is difficult to control. Despite the significant progress in the field of oncology and the emergence of new therapies, therapy resistance is a feature of several metastatic tumours and a life-threatening situation that is challenging to overcome. The understanding of the mechanisms that lead to metastasis and treatment resistance is crucial, for the development of new effective therapeutic interventions.  

Introduction

Definition of metastasis

Metastasis describes an advanced cancer stage during which cancer cells spread from their original location, invade the surrounding tissue, enter the circulation system, migrate, and form new tumours to other organs of the host. The initial location is called the primary tumour for solid malignancies. 

Definition of treatment resistance

Treatment resistance occurs when cancer cells do not respond or stop responding to therapy. Multidrug resistance is the unresponsiveness of cancer cells to multiple available treatments or combinations of them, and it is one of the major causes of cancer-related deaths. 

Importance of understanding metastasis

Metastatic tumours often become resistant to available treatments, leaving patients with no alternative options in some cases. Therefore, it is urgent to understand the biological events leading to metastasis and eventually to the broad unresponsiveness of cancer cells. In this way, new effective therapeutic interventions can be developed for patients.¹

Stages of metastasis

Distinct sequential events occur during metastasis.^2,3 These include:

Invasion 

Cancer cells of the primary organ or tissue mobilise, and disrupt the basement membrane, which is a form of extracellular matrix, separating epithelial cells from the connective tissue. Subsequently, they lyse the surrounding tissue moving to different layers of the tissue.  

Intravasation

Some of those cancer cells reach and enter blood or lymphatic vessels.

Circulation

After entering the circulatorysystem some cancer cells adapt and survive in the new environment.

Extravasation

Eventually, they exit the vessels and enter new organs or tissues, seeding them by creating new conjunctions with cells or the extracellular matrix.

Colonisation

Cancer cells that adjust to their new microenvironment, initially form small structures called micrometastatic lesions that are dormant and display small growth. Eventually, these lesions exit the dormant status and proliferate, generating new clinically detectable tumours.

Why does metastasis occur

There are two distinct proposed models explaining the phenomenon of metastasis. The 'stochastic' model suggests that metastasis is an aftermath of evolution at a cellular level. This means that some normal cells of the tissue accumulate several random genetic alterations as they proliferate until one clone eventually becomes carcinogenic and invasive. 

According to the 'hierarchical' model, a small number of cancer cells of the initial tumour presents stem cell properties. These cancer stem cells can stay in a steady, non-proliferative state for long periods, but they can also self-renew or give rise to distinct cancer cells.  

Both models provide possible explanations for the observed tumour heterogeneity and resistance to therapy in metastatic tumours.⁴

Biological hallmarks of metastasis

The survival of cancer cells during invasion, extravasation, and colonisation is supported by two distinct events. Firstly, the high genetic heterogeneity observed in tumours, results in clones that are more adapted to their microenvironment. Secondly, dynamic non-genetic alterations allow them to respond and adjust to pressures of their 'ecosystem', meaning other tissue components or circulation.²

 The biological traits of metastasis include:

Genetic mutations

Cancer cells accumulate alterations in their genes. These alterations allow them to proliferate without control, and to avoid cell death. 

Epithelial-mesenchymal transition (EMT)

A determining event for metastatic potential  is the acquisition of mesenchymal characteristics by cancer epithelial cells. This allows them to mobilise and migrate. 

Adaptation to tumour microenvironment

Metastatic cells display great plasticity, which means that they can adapt to a variety of surroundings and pressures. Cancer cells migrate from the primary tumour, through the circulation system, to a new tissue, where a completely different microenvironment exists. Metastatic cancer cells adjust their metabolic needs accordingly, lyse physical barriers of the tissue, avoid the destruction of immune cells of the host and connect with completely different cell types of the new tissue. 

Biological hallmarks of treatment resistance

Different factors either within the cells or within the tumour microenvironment contribute to treatment resistance,⁵ and are listed below:

Intrinsic resistance

Intrinsic features of the cancer cells leading to treatment resistance exist before treatment administration. Tumours display heterogeneity, meaning that cancer cells accumulate distinct genetic alterations, some of which allow them to withstand specific treatments. 

Acquired resistance

Following treatments such as radiation, some cancer cells might accumulate further genetic alterations, equipping them to survive treatments to which they were initially sensitive. 

Tumour microenvironment

The surrounding environment of cancer cells can also protect them against therapeutic reagents through physical barriers or other cell components. The vascular system, central to delivering drugs to tumours, can be incomplete in various areas of a tumour, resulting in a non-exposure of some cancer cells to therapy. Immune cells that fail to recognise and eliminate cancer cells, a phenomenon called immune suppression, also support the emergence of resistance. 

Other parameters

The size and growth rate of the tumour are also factors influencing the effect of a drug on cancer cells. However, this can vary between different tumour types with several studies suggesting that a bigger tumour burden is favourable for the elimination of cancer cells, and other studies showing that it is favourable for acquired resistance.⁶

Current and emerging therapies

Current and emerging therapeutic strategies focus on the biological hallmarks of metastasis and resistance, aiming to find unique vulnerabilities to make the resistant tumours druggable. 

Targeted therapies

Targeted therapies refer to the administration of treatments according to the specific characteristics of the cancer cells. An understanding and classification of the traits of the tumour, including genetic and non-genetic factors is important to decide a suitable therapy. Small molecules or antibodies target specific proteins of the cancer cells.⁷

Immunotherapy

Immunotherapeutic strategies exploit the ability of the immune system of the host to target and destroy cancer cells. They aim to reverse immunosuppression that supports the occurrence of resistance.⁸

Combination therapies

Due to the great heterogeneity and plasticity of the tumours, not all cancer cells of a patient are vulnerable to a specific treatment. Therefore, it is often necessary to combine different therapeutic strategies to prevent or overcome resistance.⁸

Personalised medicine

Importantly, all interventions should be adjusted to the specific features of each individual. Therefore understanding the biological mechanisms of tumours of each patient is central to developing a personalised treatment.⁹

Future directions

Despite all recent advances metastasis and treatment resistance remain challenging in oncology and cause the majority of cancer-related deaths. Early detection of tumours before they become metastatic can be life-saving. Therefore, the discovery of biomarkers that will identify the disease early is important, as well as the prediction of treatment response. Additionally, research is important for understanding the biology of metastatic cells. Hopefully, the development of new innovative treatments and improved drug delivery will contribute to overcoming the hurdle of treatment resistance.⁹

FAQs

How long does it usually take for a tumour to become metastatic?

Currently, there is no clear answer to this question, as it depends on several factors including the type of cancer and other patient characteristics, such as their immune system. Several tumours remain benign for years before they gain metastatic potential. Moreover, once invasion starts, the forming of micrometastatic lesions in other organs can form within days, however clinical detectable metastasis can occur within weeks or years.¹⁰ 

In which organs do cancer cells metastasise?

Each cancer type is possible to metastasise to specific organs, according to the sex and age of the individuals. For example, prostate cancer is a source of bone metastasis, while other sites remain minimally affected.¹¹

Summary

Basic and clinical research in oncology has provided new available treatments for a variety of cancer types. Despite the significant progress, treatment resistance is a feature of metastatic cancer that leaves clinicians with few alternatives. Therefore, the understanding of the biological events that govern metastasis and resistance is a priority for future research. In this way, through the scope of personalised medicine,  emerging new treatments can target specific vulnerabilities of metastatic tumours and prevent or reverse their unresponsiveness.