HC10: General principles: metastasis

Historical perspective

Metastasis is Greek word, which in medical use describes the shift of disease from one part of the body to another. It is mainly used in context of cancer.

Jean Claude Recamier:

In the 19^th century, Jean Claude Recamier recognized that cancer can spread from a primary tumor.

Stephan Paget:

Stephan Paget came up with the seed-and-soil theory. He stated that the growth of a tumor is not a matter of chance, but that there must be an affinity between the tumor cells and the site where they are metastasizing.

Sister Mary Joseph node:

Sister Mary Joseph noticed that a tumor in the umbilicus usually is a metastasis of a tumor elsewhere → a sister Mary Joseph node is a secondary lesion in 1-3% of abdominal cancers. Its metastatic route is unclear.

James Ewing:

In 1929, James Ewing states that metastatic dissemination occurs by purely mechanical factors.

Mechanistic theory:

The mechanistic theory states that mechanical forces and circulatory patterns between the primary tumor and the secondary site account for organ specificity. This forms a contradiction to the seed-and-soil theory. In the end, both theories proved to be correct → depends on the cancer type.

Bernard Fisher:

In 1965, Bernard Fisher described breast cancer as a systemic disease. He stated that early-stage breast cancer can be more effectively treated by lumpectomy, in combination with radiation therapy, chemotherapy and/or hormonal therapy than by radical mastectomy. Mastectomy is an extremely invasive procedure where the breasts, muscles and lymph nodes are removed. If metastasis has already occurred, such treatment isn’t useful.

Isiah Fidler:

In 1975, Isiah Fidler stated that metastasis is the result from the survival of only a few tumor cells. The process of metastasis and invasion is comprised of several stages:

1. A primary tumor is proliferating and generating clonal heterogeneity
2. Angiogenesis takes place
3. Tumor cells start migrating from the primary site
4. Tumor cells enter lymphatic and blood vessels → are transported throughout the body
5. Tumor cells start interacting with other cells, including immune cells
6. When they arrive at different organs, tumor cells leave blood vessels
7. Tumor cells grow in a new environment

This is a complex process which consists of different steps. A tumor clone needs to acquire all these features, which is quite difficult. One of the ways they can do this is through genomic instability. Once a tumor cell has acquired the 10 hallmarks of cancer, it can metastasize.

Robert Weinberg and Jean Paul Thiery:

In 2002, Robert Weinberg and Jean Paul Thiery introduced the concept of EMT (epithelial to mesenchymal transition). This concept is specifically applied to epithelial tumors:

1. Epithelium is located on top of the basal membrane, mesenchymal cells are located beneath the basal membrane
2. If epithelial tumors want to grow in the mesenchymal section, they need to acquire features that are similar to mesenchymal cells to be able to survive the environment

Mechanisms

EMT:

EMT most often refers to functional characteristics gained during malignant progression rather than complete morphological changes. It is the transition from epithelial to mesenchymal cells:

• Epithelial cells
  • Cell polarity
  • Cell adhesion
    • To each other and to the ECM
  • Stationary
  • High level of E-cadherin
  • Low level of N-cadherin
• Mesenchymal cells
  • No cell polarity
  • Loss of cell adhesion
  • Ability to migrate and invade
  • Low level of E-cadherin
  • High level of N-cadherin
    • More affinity to the new environment

E-cadherin is a tumor suppressor. It is characterizing for epithelial cells. When E-cadherin is lost, cells become more detached and free to migrate. E-cadherin loss can also impact signaling → activates Wnt-signaling. β-catenin in healthy cells also binds to E-cadherin as part of the cell’s cytoskeleton. When E-cadherin is lost, β-catenin doesn’t bind E-cadherin anymore and it becomes free to mediate activation and transcription of Wnt-target genes.

Invasion:

Metastasis requires invasion of adjacent healthy tissues in a primary tumor as well as at the metastatic site → basal membranes around cells have to be destroyed and an ECM around cells has to be made. This can be done by certain enzymes → matrix metallo proteinases (MMPs).

MMPs have a number of target proteins which are normally part of the extracellular space. Malignant tumors can produce enzymes which digest these proteins. This makes it possible for tumors to rearrange the tissue so they can grow.

Integrins:

Integrins are a mix between extracellular molecules which have adhesive properties and signaling mediators → they have structural and signaling functions. Integrins bind components of the ECM → can tell whether the cell is in its right context or not:

• In healthy epithelial tissues, cells express integrins which can bind extracellular molecules which are located in the epithelium → tell the cell that it’s in its right spot
• If a cell moves to a different environment, the composition of the ECM changes → integrins no longer recognize the molecules in the ECM → stop providing positive signals to the cell → cell death
• Tumor cells change their integrins so that they’re able to recognize ECM components from different tissues → colonize new environments

Signaling pathways controlling metastasis

The TGF-β pathway is a major regulator of invasion and migration processes in cancer cells. TGF-β is an immune suppressive growth factor that epithelial cells can activate. When activated, TGF-β is associated with a number of molecules that are linked to malignant tumors, for instance integrins and the suppression of E-cadherin.

Colorectal cancers can be divided according to their gene expression profile, of which one is strongly linked to the expression of TGF-β. This is CMS4 mesenchymal cancer, which occurs in 23% of cases and is linked to a worse relapse-free and overall survival.

Stromal cells:

Tumor cells are not only composed of cancer cells. Stromal cells play an important role in activation of metastasis. Molecules that alter the phenotype of normal fibroblasts can be produced, such as TGF-β. Once the phenotype of these fibroblasts is modified, they start cooperating with the tumor cells in providing features that support malignant behavior patterns:

• Immune suppression
• Pro-tumorigenic signals
• Angiogenesis

Angiogenesis:

Oxygen-sensing by HIF-1α is a major mechanism regulating angiogenesis. HIF-1α is a central molecule in the hypoxia pathway and reacts when cells require oxygen → when there’s a shortage of oxygen, HIF-1α does multiple things:

• Supports angiogenesis of blood vessels to the site
• Supports cell survival in harsh conditions
• Induces the consumption of glucose

This helps cancer cells increase their invasive capacity.

Metastatic routes

There are 3 paths for the development of metastasis → malignant cells can spread to different sites by invading into:

• Lymphogenic route: through the lymphatic system
• Hematogenic route: through blood vessels
• Migration of tumor cells through body cavities

Angiogenesis doesn’t only occur for blood vessels → lymphangiogenesis also exists.

Lymph node versus distant metastasis:

There isn’t a sequentional process between the establishment of lymph node metastasis and the metastasis of distance. If colorectal cancer occurs in a patient with both lymph node metastasis and liver metastasis it isn’t necessarily true that the tumor cells that grow in the lymph nodes are the same as those in the liver.

Common metastatic sites:

Several common metastatic sites are:

• Lung
  • Can occur with a wide range of malignant neoplasms
  • Sarcomas
    • E.g. osteosarcoma
  • Carcinomas
    • E.g. breast, stomach and large intestine carcinomas
  • Kidney
    • Cannonball metastatic pattern
  • Testis
    • E.g. malignant teratoma
• Liver
  • Common site for colorectal cancer
    • Portal vein
  • Bronchial carcinoma
  • Breast carcinoma
  • Melanoma
  • Pancreatic cancer
• Bone
  • A bit more restricted
  • Bronchial carcinoma
  • Breast carcinoma
  • Thyroid carcinoma
  • Renal carcinoma
  • Prostate cancers

Metastatic patterns:

Tumors can be distinguished by their ability to metastasize at different places. This can say something about the circulation of the organ where the tumor is primarily developed. Lung cancer is notorious for its ability to metastasize to different sites. It needs very little time to do this. Colorectal cancer has a very organized metastatic route → organs involved most often in metastatic colon cancer are:

• Liver: 80%
• Lung: 50%
  • Secondary to metastasis in the liver
• Bones: 30%

Tumors like prostate cancer have a very strong presence for different sites. Often, metastasis is established in bones.

Types of cancer:

Metastatic sites and types of cancer are:

• Carcinomas
  • Local invasion and spread
    • E.g. ovarian cancer
  • Regional lymph-nodes
  • Supra-regional lymph-nodes
  • Haematogenous spread
    • Lung, liver, bone and brain
• Sarcomas
  • Local invasion and destructive growth
  • Haematogenous spread
    • Lung and liver
  • No lymphatic spread
• Lymphomas
  • Lymph nodes
  • Haematogenous spread
    • Liver, bone marrow, spleen