Curing cancer - How metastases arise
Part 3b-1 - What cells normally migrate
Part 1 of this series discussed the basics of metastatic disease.
Part 2 discussed features of human biology that are important in understanding cancer and metastases.
Part 3 discussed basic principles of how these features are altered during the development of cancer and metastases, with specifics to be discussed in parts 3a through 3d.
Part 3a discussed normal (physiologic) cell division and how this cell property is altered during malignant transformation.
Part 3b-1 discusses normal cell migration. Related discussions for nonscientists are at
- Cell migration in the embryo and fetus (how metastases arise, part 3b-1a)
- Cell migration in children and adults (how metastases arise, part 3b-1b)
Cell migration is an evolutionarily conserved activity essential for development and function in humans, particularly for embryogenesis, wound healing, immune response and blood vessel formation (Kurosaka 2008). Its major components have been functionally conserved in evolution for over a billion years, from protozoa (single celled organisms) to mammals (Kurosaka 2008). Cells migrate individually or collectively (i.e., as sheets or clusters of cells).
What cells migrate?
The migration of cells over short and long distances determines their correct positioning during embryonic organogenesis and in adult tissues and organs:
To initiate migration in a developing organism, individual cells receive signals, which set in motion the complex and highly coordinated molecular machinery that drives these cells to move in the right direction with the appropriate speeds and to arrive at their destinations at exactly the right time (Kurosaka 2008).
Migration defects during embryogenesis cause severe embryonic malformations, including early embryonic death, neurological disorders, congenital heart disease and physical and mental retardation (Kurosaka 2008).
Migration is physiologically normal for these conditions and cells:
Embryonic cells migrate at week 3 of embryogenesis during gastrulation, which is characterized by embryonic cell movement and reorganization to form the 3 primary germ layers: ectoderm (the outer tube that forms the skin and nervous system), endoderm (the inner tube that forms the gastrointestinal and respiratory tracts) and mesoderm (the middle layer that forms muscle, bone, the heart and circulatory system, cartilage and other connective tissue).
The blastula reorganizes into the gastrula, which develops 3 germ layers: the ectoderm, endoderm and mesoderm. The archenteron is the primitive digestive tract that develops into endoderm and mesoderm.
The cells in these 3 germ layers then migrate to their target locations where they differentiate into distinct cell populations that make up various embryonic tissues or organs. Tissue and tube formation is achieved through collective cell migration (Nikolaou 2020).
Migration of cells in 3 germ cells occurs in the embryo and fetus.
This diagram shows the adult equivalents of these locations.
Neural crest cells and their derivatives migrate collectively through the embryo, forming neurons and glia (supporting) cells, the adrenal medulla, skin pigmented cells and the skeletal muscle and connective tissue components of the head.
- During early stages, neuronal precursors of the neural crest lineage follow the same migration mechanisms as other mesenchymal cells but after differentiation, neuronal cell bodies become stationary and only their neurites migrate (Kurosaka 2008).
Migrating neuronal cells
Primordial germ cells migrate as individual cells towards the genital ridges, which become the testes and ovaries (Kanamori 2019).
Primordial germ cells (PGC) originate in the allantois, part of the placenta, and migrate to the genital ridges. They rarely migrate to the brain and can cause tumors.
Epithelial cells in adults migrate during wound healing.
Wound closure is characterized by migration of neutrophils, macrophages and epithelial cells (Leoni 2015).
Adult epithelia, from which carcinomas arise, show limited migration and tend to remain attached to neighboring cells in an organized way (Nikolaou 2020).
Epithelial cells are connected to each other by various mechanisms, which prevent epithelial cell migration under standard conditions.
Epithelial cells in adults can migrate, however, as part of gut homeostasis; in the small intestine, cells near the base of villi proliferate and move toward the top of the villi.
Adult stem cells are rare cells present in almost all adult mammalian tissues and are responsible for tissue maintenance and repair (de Lucas 2018).They reside in a quiescent state in specific tissue niches until activated by tissue environmental signals. Then they undergo asymmetric cell division: one daughter cell creates a committed clone that proliferates and differentiates (multipotency capability) and the other remains undifferentiated, contributing to the stem cell’s self renewal capacity. Stem cells can also migrate, beginning in early embryogenesis. In children and adults, adult stem cells are one of the few cell types with the capacity to migrate under appropriate stimuli.
White blood cells migrate individually and collectively for wound healing. Their migration is also important for immune cell development and immunosurveillance (Delgado 2022) as well as to maintain tissue homeostasis, respond to injury / infection and eliminate pathogens (George 2023).
Migrating white blood cells
Mesenchymal stem cells migrate as part of bone formation and bone fracture healing, although this is not completely understood (Su 2018, Fu 2019).
Migrating mesenchymal stem cells
Adult hematopoietic stem cells migrate from the bone marrow into the circulation and back to the marrow (Wright 2001).
Endothelial cells migrate as a part of angiogenesis. This involves degrading the extracellular matrix to enable the progression of the migrating cells (Lamalice 2007).
Part 3b-2 will discuss normal triggers of migration and the mechanics of cell migration.
