Contact inhibition

In cell biology, contact inhibition refers to two different but closely related phenomena: contact inhibition of locomotion (CIL) and contact inhibition of proliferation (CIP). CIL refers to the avoidance behavior exhibited by fibroblast-like cells when in contact with one another. In most cases, when two cells contact each other, they attempt to alter their locomotion in a different direction to avoid future collision. When collision is unavoidable, a different phenomenon occurs whereby growth of the cells of the culture itself eventually stops in a cell-density dependent manner. Both types of contact inhibition are well-known properties of normal cells and contribute to the regulation of proper tissue growth, differentiation, and development. It is worth noting that both types of regulation are normally negated and overcome during organogenesis during embryonic development and tissue and wound healing. However, contact inhibition of locomotion and proliferation are both aberrantly absent in cancer cells, and the absence of this regulation contributes to tumorigenesis.

Contact inhibition is a regulatory mechanism that functions to keep cells growing into a layer one cell thick (a monolayer). If a cell has plenty of available substrate space, it replicates rapidly and moves freely. This process continues until the cells occupy the entire substratum. At this point, normal cells will stop replicating.

As motile cells come into contact in confluent cultures, they exhibit decreased mobility and mitotic activity over time. Interestingly, exponential growth has been shown to occur between colonies in contact for numerous days, with the inhibition of mitotic activity occurring far later. This delay between cell-cell contact and onset of proliferation inhibition is shortened as the culture becomes more confluent. Thus, it may be reasonably concluded that cell-cell contact is an essential condition for contact inhibition of proliferation, but is by itself insufficient for mitotic inhibition. In addition to making contact with other cells, the contact-inhibited cells must also be forced to reduce its cell area under the mechanical stress and constraints imposed by surrounding cells. Indeed, it has been suggested that mechanical tension acts as an inhibitory signal for mitosis. Moreover, it is important to note that such an inhibition of mitotic activity is a local phenomenon; it occurs between a select few cells in a likely heterogeneous culture.

Untransformed human cells exhibit normal cellular behavior and mediate their growth and proliferation via interplay between environmental nutrients, growth factor signaling, and cell density. As cell density increases and the culture becomes confluent, they initiate cell cycle arrest and downregulate proliferation and mitogen signaling pathways regardless of external factors or cellular metabolism. This property is known as contact inhibition of proliferation and is essential to proper embryonic development, as well as tissue repair, differentiation, and morphogenesis. Cancerous cells typically lose this property and thus divide and grow over each other in an uncontrolled manner even when in contact with neighbouring cells. This results in the invasion of surrounding tissues, their metastasis to nearby organs, and eventually tumorigenesis. Interestingly, cells of naked mole rats, a species in which cancer has never been observed, show hypersensitivity to contact inhibition. This finding may provide a clue to cancer resistance. Furthermore, recent studies have further revealed some mechanisms of contact inhibition of proliferation and its potential implications in cancer therapy.

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