A tumor cells ceaselessly proliferate giving rise to countless clones

In the second chapter of the “Hallmarks of cancer” series we talk about the cancer cell capability to continuously sustain proliferative signalling.

As discussed in the first chapter (see here), our body works as a perfect society, in which every cell behaves in a social responsible-manner, proliferating, remaining quiescent or even dying, for the good of the organism. Arguably, the most famous characteristic of a cancer cell is the ability to perpetually proliferating without any brake.

How is this possible? To answer this question we should first understand how cells communicate and how they receive and interpret the signals in the body. We can see each cell as a little radio station. On the outer cell membrane antennas called “receptors” exist, and receive signals from the outside and transmit them back inside the “station”. This process is called signalling cascade pathway: from the outside, the external message goes into the nucleus of the cells. Each level of the cascade is mediated by intracellular protein, which transmit to the nucleus and activate gene programs that “instruct” the cells on what to do. Initial extracellular signals, are made by molecules called “ligands”, which can come from different sources:cancer-signaltransduction-25-728

  • Distant organ (endocrine signalling)
  • The same tissue where the cell resides (paracrine signalling)
  • The cell itself (autocrine signalling).

Each cell receives thousands of signals at time. The sum of all the obtained information determines how the cell responds. It is really difficult to study how these processes are regulated. Indeed, most of the signals, which dictate cell number and even position into a tissue, act in a paracrine way and for a short period of time; in other words, is really difficult to access them experimentally in vivo. Paradoxically, since it is easier to experimentally investigate such mechanisms, we know much more about the communication existing in the tumor context.

Several studies have shown that cancer cells can sustain proliferative signalling in a number of ways:

  • They can auto-produce factors which stimulate their growth; they can pretend to receive an external signals that says, “PROLIFERATE”.
  • They can “convince” the normal cells around (also called tumor-associated cells) to produce and release the ligands needed to proliferate and grow (grow means increasing their size).
  • They can increase (up-regulate) the number of receptors on their surface and respond to extremely low concentration of proliferative signals. The same can be achieved through mutations that render the receptor always active, and thus, independent from the presence of the ligand.

Receptors communicate to the cells by virtue of various intracellular mediators, which transmit the signals to the nucleus. All these mediators can be mutated and hyper-activated in cancer cells, making them completely independent from any external factor and masters of their own destiny.

In summary, tumor cells can acquire powerful features that allow them to produce growth factor themselves, or to convince surrounding normal cells to do so, and can mutate several key proteins, such as membrane receptors or intracellular mediators, to sustain a ceaseless proliferation.

Worth mentioning, several signalling cascade pathways are involved in neoplastic transformation and, while some pathways are shared between different tumors, others are tumor type-specific. This is one of the reasons why dissimilar cancers are treated differently, or have a distinctive levels of aggressiveness.

However, evolution provided each cells with several control mechanisms to avoid they could easily start to proliferate without any control. These signals are generally called “growth suppressors” and tumors cells must shut them down to fully achieve proliferative independency.

How do they do that? We will answer in the next chapter of the series.

Davide Mangani