Where does cancer come from?

The origins and classifications of cancer.

Origins of Cancer

Cancers are caused by masses of cells that grow uncontrollably, forming tissues called tumors.

Originally, tumors were considered “foreign bodies” that had taken root inside a person, much like bacterial infections. However, through histological studies (aka looking at tissues under the microscope), scientists have identified that tumors derive directly from the normal tissues in which they are first discovered.

Some tumor cells can move from the primary tumor through the body’s blood or lymph system to form new tumor settlements called metastases. This leads to a segregation of tumors based on the aggressiveness of growth— tumors that stay in one place are benign, while those that invade other tissues are malignant. However, tumors develop progressively and achieve gradations between benign and malignant. The spectrum goes as follows:

normal → hyperplastic or metaplastic → dysplastic → neoplastic → metastatic

~ Relatively Benign ~

Hyperplastic growth occurs when there is an excessive number of normal cells in a tissue.

Metaplastic growth indicates tissues with other cell types not normally found at the tissue site (epithelial transition zones/epithelial-mesenchymal transition).

~ Starting to grow from benign to malignant ~

Dysplastic growths start to have abnormal cells; they grow to a point and stop growing. Examples include polyps and warts.

Neoplastic growths include abnormal cells that are invasive; some use neoplasm synonymously with malignant tumors.

Through lineage tracing studies, cancer tumors were found to be monoclonal, or derived from a common ancestor cell that crossed from normal to abnormal growth. However, the finer details are more complex. For example, there could very well be 10 normal cells in a body that together crossed from normal to abnormal, but after a period of time, one of the malignant cell lines outgrew the others and dominated the tumor mass.

Major Classifications

There are more than 200 subtypes of cancer in existence, and scientists are discovering more every day. With so many tumors arising in various organs and tissues, it’s hard to classify cancer purely by its morphology or molecular attributes. Fortunately, cancer can be systematized into three major classes by  (1) what kind of cell becomes cancerous (cell differentiation state), (2) where it arises (embryonic origin), and (3) how it behaves (biological behavior).

1. Epithelial

The majority of cancers are formed from epithelial tissues. Epithelia are sheets of cells that line the outer layer of a body’s surface (skin) and the walls of cavities and channels (stomach). Beneath the epithelial cells is the basement membrane, which separates the epithelia from underlying connective tissue, the stroma. Another basement membrane separates the stroma from the endothelium, which lines capillaries and vessels.

Epithelial cells arise from all three primitive layers in the early vertebrate embryo, the ectoderm, mesoderm, and endoderm.

Ecto = outside. Skin & internal linings.

Meso = middle layer. Muscle & connective tissue

Endo = inside. Internal organs.

Epithelia line different organs formed in all three layers.

Human embryonic development. Credit: Shutterstock

Epithelial cells give rise to the most common human cancer, carcinomas. They are responsible for more than 80% of cancer-related deaths in the US! There are two types of carcinomas

Squamous Cell Carcinomas: tumors that arise from epithelial cells forming protective layers (eg. skin).

Adenocarcinomas: tumors that arise from epithelia with specialized cells that secrete substances into cavities (eg. stomach, lung).

Esophagus carcinomas and adenocarcinomas. Credit: Osmosis

The epithelia in some organs, including the lung and uterus, can give rise to both squamous cell carcinomas and adenocarcinomas. They’re often not mutually exclusive!

2. Non-epithelial

Non-epithelial tissues make up another majority of malignant tumors.

Three types of cancers arise from non-epithelial cells:

Soft Tissue Sarcoma. Credit: Mayo Clinic

Sarcomas: Sarcomas are formed from mesenchymal cell types, including bone cells (osteoblasts), cartilage (chondrocytes), muscle cells (myocytes), and fat cells (adipocytes). They make up less than 1% of the cancers seen in patients.

Types of Blood Cancer and their Treatment Options. Credit: Onco Life Cancer Center

Blood & Immune Cancers: The cancers arise from blood and immune cells, including red blood cells (erythrocytes), antibody-secreting (plasma) cells, and T and B lymphocytes. The cancers include leukemias and lymphomas. They are responsible for 7% of cancer-related deaths.

Glioblastoma (brain cancer) in top right corner of brain. Credit: Medscape

Neuroectodermal Cancers: The neuroectoderm is the part of the embryonic ectoderm that develops into the brain, spinal cord, and peripheral nervous system. Neuroectodermal cancers include gliomas, glioblastomas, and medulloblastomas. While they only comprise 1.3% of all diagnosed cancers, they are responsible for 2.5% of cancer-related deaths.

3. Mixed

This category is for tumors that don’t fall perfectly into the above-two groups. Like always, there are exceptions.

Melanomas: Melanomas are caused by melanocytes, pigment cells in the skin and eye. Melanocytes originate from the neural crest but aren’t part of the neuroectoderm; instead, melanocytes wander during development into the skin and eyes.

Small Cell Lung Carcinomas (SCLC): SCLCs have cells with neurosecretory behavior, though scientists believe the cells to have emerged from the endoderm.

Teratomas: Only 10,000 teratomas are diagnosed worldwide annually, but they’re incredibly interesting tumors that arise from germ cell precursors that fail to migrate properly during embryogenesis. Germs cells are pluripotent, so teratomas often contain different types of tissue within one tumor, including hair, nails, and bone.

Cells of Unknown Primary (CUP): In about 2-4% of cancers, the tumors have shed their tissue-specific differentiated traits of ancestor cells. The tumors are anaplastic, and it’s no longer possible to identify which tissues they arose from.

Here’s a diagram to picture the entire classification system:

Visualization of the tumor classification hierarchy. Credit: The Biology of Cancer by Robert A. Weinberg

If you’re new to cancer and science, I know this was incredibly info-heavy. Not all posts will be like this! Stick with it, and I promise you’ll learn a crazy lot!

Sources for Further Reading

The Biology of Cancer - Robert A. Weinberg

Title Image Credit: The Cancer Miracle Isn’t a Cure by Harvard Magazine