# Hallmarks of Cancer (Activating Invasion and Metastasis)

Invasion and metastasis are fundamental hallmarks of cancer, representing the ability of the cancer cells to spread from their site of origin to distant tissues and organs. These processes are central to cancer's lethality, accounting for the majority of cancer - related deaths, and marking an important barrier to effective treatment.
These processes enable cancers to establish secondary tumors, contributing to the majority of cancer-related deaths. Understanding and targeting the mechanisms of invasion and metastasis remain pivotal in cancer therapy and research.

## Mechanisms of Invasion
### Epithelial-Mesenchymal Transition (EMT)

Epithelial-mesenchymal transition (EMT) is a process where epithelial cells lose their adhesive properties and gain a more mobile, invasive phenotype. This change is regulated by signaling pathways like TGF-B, Wnt, and Notch as well as transcription factors such TWIST, SNAIL, AND ZEB. EMT allows cancer cells to invade surrounding tissues and spread more effectively.

### Degradation of the Extracellular Matrix (ECM)

To invade nearby tissues, cancer cells cells secrete enzymes such as matrix matalloproteinases (MMPs) that degrade the ECM and basement membrane. This breakdown creates pathways for cancel cells to migrate and infiltrate new areas.

#### Tumor Microenvironment

The tumor microenvironment, composed of stromal cells, immune cells and singaling molecules, supports invasion by creating good and favorable conditions for tumor cell migration. For example, cancer-associated fibroblasts (CAFs) produce substances that remodel the ECM and promote cancer progression

### Local Tissue Invasion

Epithelial-to-mesenchymal transition (EMT) is a biological process in which epithelial cells lose their polarity and cell-cell adhesion properties and acquire mesenchymal traits, such as enhanced motility and invasiveness. This transformation plays a critical for various physiological processes, such as embryonic development, wound healing, and tissue regeneration. However, in cancer, EMT is often hijacked to promote tumor progression and metastasis. During EMT, epithelial markers like E-cadherin are downregulated, while mesenchymal markers such as N-cadherin and vimentin are upregulated. This change enables cancer cells to detach from the primary tumor, invade surrounding tissues, and ultimately spread to distant locations in the body by entering the bloodstream or lymphatic pathways.
Cancer cells undergo several changes that enable them to invade surrounding tissues. A primary mechanism is the downregulation of E-cadherin which is an epithelial adhesion molecule that helps maintain cell-cell adhesion. Loss of E-cadherin reduces cellular cohesion, allowing cancer cells to detach from the primary tumor. This is a hallmark of EMT, during which cancer cells acquire mesenchymal traits, such as increased motility and invasiveness.

## Mechanisms of Metastasis
### Intravastation

Intravasation is the process where tumor cells enter blood or lymphatic blood vessels, allowing them to travel to distant parts of the body. This step is important in the metastatic journey as it enables tumor cells to leave their original site and circulate through the body. pro-angiogenic factors like VEGF, along with interactions between cancer calls and the vessel walls, make it easier for tumor cells to penetrate into the bloodstream or lymphatic system. By gaining access to these transport networks, cancer cells increase their ability to spread and form new tumors in distant tissues.

### Circulating Tumor cells (CTCs)

When cancer cells enter the bloodstream, they are known as circulating tumor cells (CTCs). To protect themselves from being detected and destroyed by the immune system, these cells often group together in clusters or cover themselves with platelets. This protective strategy increases their chances of survival and makes it easier for them to spread to other parts of the body.

### Extravasation and Colonization

Extravasation occurs when circulating tumor cells leave the bloodstream and invade new tissues, guided by molecules like integrins. Integrins help the cells attach and move into their new environment. Once settled, cancer cells form a metastatic niche that helps them grow and establish a new tumor in a new location.

### Roles of Biomarkers In Tumor Metastasis
#### E-cadherin

E-cadherin is an epithelial adhesion protein that plays an essential role in maintaining tissue structure by facilitating cell-cell adhesion. Its downregulation is a major feature of EMT transition which is a process that is important for cancer metastasis. The loss of E-cadherin disrupts cellular adhesion, allowing tumor cells to detach from the primary site and invade surrounding tissues. This type of suppression is often mediated by EMT transcription factors such as ZEB1, Snail, and Twist, is then repress E-cadherin gene expression. Furthermore, when E-cadherin is reduced, it facilitates interactions with the extracellular matrix (ECM) which in then enhances the ability of cancer cells to migrate and invade surrounding tissues. By promoting these interactions, E-cadherin is able to support cellular motility and aid tumor cells navigate the tissue structures which drives metastasis. Research emphasizes E-cadherin as a major biomarker in metastatic cancers such as breast and colorectal cancers. Low levels of E-cadherin are often linked to poor clinical outcomes, therapy resistance and aggressive tumor phenotypes.