Targeted Therapy: What Are Invasion and Metastasis in cancer?

Targeted cancer therapy is a specific method of treatment for cancers, by identifying and targeting the cancer-causing factors (hallmarks) in the particular cancer. Targeted therapy medications do not directly kill the cancer cells, but work on the cellular level to stop their growth and prevent cancer from spreading to other parts of the body.

Cancer target therapy consists of two forms of medications:

• Small molecule drugs: Minute particles that attach to proteins on the cell surface or get into the cell and modify its activity.
• Monoclonal antibodies: Lab-produced antibodies that are too large to get inside the cell, but work on the cell surface to activate the immune system.

Cancer is a unique group of diseases caused by uncontrolled growth of aberrant cells. Cancers arise due to mutations in the growth-modulating genes in some cells. Genetic mutations may be inherited or caused by environmental factors, certain viral infections, or sometimes a combination of factors that cannot be precisely pinpointed.

Human cell growth is a tightly regulated process dictated by inter-related cell-signaling mechanisms. Normal cells grow, divide into two daughter cells, migrate to different parts of the body, and mature into cells with specific functions (differentiation).

Normal cells also die in an orderly manner (apoptosis) when they grow old, get damaged or because they are simply no longer needed. Cancer cells don’t follow these rules. Cancer cells evade apoptosis and keep growing nonstop. Cancers can originate anywhere in the body and spread by processes known as invasion and metastasis.

Many cancers form an abnormal lump of tissue growth called tumors. Tumors grow by subverting normal cell processes to sprout new blood vessels, and recruiting nearby normal cells to aid in their growth. Tumors are termed to be malignant when they invade and metastasize.

Invasion

Normal cells stop growing when they come into contact with the nearby cells, in a process known as contact inhibition. Tumor cells continue to grow and overrun their natural space, crowding out the normal cells and starving them of oxygen and nutrients. The tumor cells then penetrate the neighboring tissue to continue growing, which is known as invasion.

Metastasis

Metastasis is the process by which cancer cells migrate and spread to other parts of the body. Human tissue is made up of primarily two types of cells:

• Epithelial cells: Cells that adhere to each other in layers and are also anchored to a supportive structure known as extracellular matrix. Epithelial cells form a layer of protective covering over the body and all the organs and glands.
• Mesenchymal cells: Mesenchymal cells are solitary stem cells produced in the bone marrow, which can migrate and mature into any type of connective tissue, blood vessels and other tissue cells as required, during growth or wound healing.

Normal epithelial cells cannot survive detached from the extracellular matrix, and undergo apoptosis. The dead cells are cleared away by immune cells known as phagocytes which engulf and digest them. Abnormal epithelial cells (skin cancers) spread through the skin and lymphatic system. 

Tumor cells develop the ability to transform into abnormal mesenchymal cells and disengage from the extracellular matrix. The stem-cell like tumor cells get into the bloodstream or the lymphatic system, migrate to other parts of the body, and start forming new tumor growths.

There are several proteins and cellular signals that tumor cells employ for promoting invasion and metastasis. Many therapies targeting invasion and metastasis are in development.

TGF-B inhibitors

Transforming growth factor beta (TGF-B) is a protein (cytokine) secreted by all types of white blood cells. TGF-B family has many proteins that play multiple roles in regulating cell growth, differentiation, migration, apoptosis and extracellular matrix production.

TGF-B proteins play a role in inhibiting growth in the initial stages of tumor, by releasing inflammatory cytokines. Genetic mutations in the cancer cells disrupt the TGF-B signaling pathways and negate the inhibitory effect. TGF-B also suppresses immune response to promote healing which helps the tumor evade immune surveillance and grow.

Other roles of TGF-B include promotion of epithelial-to-mesenchymal transition, formation of new blood vessels (neo-angiogenesis) and extracellular matrix, and migration, which enable the tumor cells to invade other tissue and metastasize. Many types of cancer have been found to secrete increased levels of TGF-B.

Both small molecule inhibitors and monoclonal antibody therapies targeting TGF-B inhibition are in clinical trials.

IGF-1R inhibitors

Insulin-like growth factor (IGF) is a signaling pathway that regulates fetal growth. IGF-1, IGF-2 and insulin are hormone molecules that attach to their respective protein receptors (IGF-1R, IGF-2R, IR) on cell surfaces and activate them. IGF-1R regulates the growth of skeleton and other organs in the fetus, while IR regulates the glucose metabolism in the cell.

Both IGF-1R and IR stimulate cell division and have been found to promote metastasis in many types of cancers. Several IGF-1R inhibitors and IR inhibitors are in various stages of clinical trials.

SRC SMI

The proto-oncogene c-SRC encodes SRC protein, a type of intracellular protein known as non-receptor tyrosine kinase (NRTK). A proto-oncogene is a gene that has a high potential for causing cancer if it mutates into an oncogene.

SRC kinases play an important role in cell division, adhesion, migration, invasion and metastasis. High levels of SRC proteins have been found in many types of cancers.

Following are the FDA-approved small molecule inhibitor therapies targeting the SRC protein:

• Dasatinib: Approved for two types of invasive/metastatic cancers:
  • Imatinib-resistant chronic myeloid leukemia
  • BCR-ABL positive acute lymphoblastic leukemia
• Bosutinib: approved for chronic, accelerated or blast-phase Philadelphia positive chronic myeloid leukemia

The above two therapies are also being evaluated for treating other metastatic cancers. Many other small molecule inhibitors are in clinical trials.

FAK inhibitors

The focal adhesion kinase (FAK) is a type of non-receptor protein kinase that regulates signaling pathways essential for cell adhesion, migration, proliferation and death. FAK also acts as a scaffold for connecting the cells to the extracellular matrix.

When stimulated by growth factors, FAK activates many other proteins including the SRC protein, promoting metastasis. Excessive levels of FAK are found in many types of cancer. Currently, small molecule inhibitors of FAK are in early-phase of trials.