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Cell invasion - how do cancer cells detach from the tumor and establish metastases?

The institute's scientists developed a new imaging technology, and revealed through it the way in which "legs" develop on cell membranes. These legs destabilize the material between the cells and the tissue, and play a central role in the spread of metastases

Lung cancer cells. Illustration: shutterstock
Lung cancer cells. Illustration: shutterstock

The question: How do cancer cells detach from the tumor and establish metastases?

Findings:

Cancer cells, which are released from the primary tumor in which they were formed, tend to penetrate into blood vessels or lymph, and through them they spread throughout the body. Some of the cells that survive this complex and arduous journey manage to get out of the blood or lymph vessels, invade the nearby tissues, and develop metastases in them. The formation of metastases is, in many cases, the fatal stage of the tumor process. In a study recently published in the scientific journal Scientific Reports, scientists from the Weizmann Institute of Science revealed the way in which tiny bumps are formed on the surface of cancer cells, and how these bumps help the cancer cells to spread.

Prof. Benny Giger and research student Or-Yam Varach, from the Department of Molecular Cell Biology at the Weizmann Institute of Science, are investigating the mechanisms that enable the invasion and migration of cancer cells. In their work, they focus on those tiny protrusions - called "invadopodia" - and function as a kind of "invasive legs" that are able to undermine the substance that is between the cells in the tissue, penetrate through it, and thus help the formation of metastases in the body. Prof. Giger and his group members knew that an invasive foot appears in cells when they come into contact with the intercellular tissue. According to the accepted model, in order to penetrate this compressed tissue, the cells stick to it, and weaken it using special enzymes they produce. After softening, the invasive leg lengthens - and penetrates the tissue. But how can the invasive habit, at the same time, both soften the tissue and stick to it?

In the first stage, the scientists showed that the invasion is carried out in stages. The areas of adhesion to the intercellular tissue are temporary structures, which bind the cell to the intended penetration site, and "mark" the enzymatic softening area. With the breakdown of the intercellular tissue, the contacts between the cell and the tissue also disappear, and the invasion moves to the penetration phase. At this stage, a cylinder-like protrusion develops and elongates in the center of a bundle of the protein actin - one of the main support proteins of the cell skeleton, and the elongation of the bundle pushes the invasive leg into the neighboring tissue. Although this explanation is consistent with the observations made in invasive cells, it does not explain why the elongation of the actin bundle causes a push of the cell membrane, but does not exert a force, for example, towards the center of the cell.

With the breakdown of the intercellular tissue, the contacts between the cell and the tissue also disappear, and the invasion moves to the penetration phase. To examine the two ends of the elongated actin bundle, the scientists developed a new imaging technology that combines the use of a light microscope and a unique electron microscope, with which they characterized the invasive leg, end to end. The scientists discovered that the actin bundle, which acts as the internal skeleton of the invasive foot, rests, at its inner end, on the cell nucleus, while distorting the nucleus and twisting it. "The main function of the cell nucleus is to store the hereditary material in the cell, but the discovery that it also participates in the processes of creating cancer metastases was completely unexpected," says Prof. Giger.

At this stage of the research, a central question remains unsolved: how much force does the invading leg exert on the tissue it invades? To answer this question, Dr. Ariel Livna, a member of Prof. Giger's group and a physicist by training, calculated the force exerted by the invasive leg, based on the distortion caused to the cell nucleus due to the elongation of the actin fibers. This calculation indicated an impressive ability of the skeleton in the core of the invasive leg to develop pushing forces, which allow the cancer cells to invade into the tissue. "By studying the physical and mechanical properties of the invasive leg action, while developing new research approaches," says Prof. Geiger, "we uncovered a detailed picture of the multi-step way in which cancer cells in a solid tumor begin their metastatic journey throughout the body."

These findings may yield answers that are essential for understanding the metastatic process, and perhaps even ways to prevent it, but they mainly raise many new questions: Does the force exerted on the cell nucleus affect its main function - the regulation of gene expression and their translation into further changes in the cancer cell? What is the molecular basis for the formation of invasive feet in cancer cells, and what determines the location and timing of the attachment and invasion process? These and other questions are at the center of the research being carried out these days.

Science books

The length of the tiny invasive foot is about 0.0005 millimeter, but the tremendous force it exerts on the tissue that surrounds it is equal to that exerted by a 20 kg dumbbell placed on a bowl of cooked noodles.

2 תגובות

  1. Now I would establish a startup that would invent a drug that counteracts the enzyme that destabilizes the intercellular tissue (what a genius I am) Is there anything willing to invest?

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