The p53 gene like the Rb gene, is a tumor suppressor gene, i.e., its activity stops the formation of tumors. If a person inherits only one functional copy of the p53 gene from their parents, they are predisposed to cancer and usually develop several independent tumors in a variety of tissues in early adulthood. This condition is rare, and is known as Li-Fraumeni syndrome. However, mutations in p53 are found in most tumor types, and so contribute to the complex network of molecular events leading to tumor formation.

The p53 gene has been mapped to chromosome 17. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the ‘stop signal’ for cell division. Thus cells divide uncontrollably, and form tumors.

Help with unraveling the molecular mechanisms of cancerous growth has come from the use of mice as models for human cancer, in which powerful ‘gene knockout’ techniques can be used. The amount of information that exists on all aspects of p53 normal function and mutant expression in human cancers is now vast, reflecting its key role in the pathogenesis of human cancers. It is clear that p53 is just one component of a network of events that culminate in tumor formation.

In a review published in the journal *Science*, Jain and Steele Laboratories colleagues Hadi T. Nia, PhD, and Lance L. Munn, PhD, describe four distinct physical hallmarks of cancer that affect both cancer cells and the tumor microenvironment, contributing to both tumor growth and the development of resistance to powerful cancer drugs.

One widely accepted model of cancer holds that a normal cell goes rogue because of genetic mutations or an environmental insult. In this model, the altered cell starts replicating out of control and takes over normal tissues, displaying eight hallmarks that include the ability to promote and sustain the growth of tumors, evade immune system attempts to suppress growth, stimulate blood flow to tumors and both invade local tissues and metastasize (spread) elsewhere in the body.

But this model fails to take into account how physical processes affect tumor progression and treatment, say the authors. In addition to the aforementioned eight biological hallmarks of cancer proposed by Robert Weinberg, PhD, from MIT, and Douglas Hanahan, PhD, from the Swiss Federal Institute of Technology in Lausanne, Jain and colleagues propose adding four distinct physical hallmarks that capture the biomechanical abnormalities in tumors: elevated solid stress; elevated interstitial fluid pressure; increased stiffness and altered material properties; and altered tissue micro-architecture.

Three decades of research in the Steele Laboratories led to the discovery and clinical translation of the first two hallmarks. “Solid stresses are created as proliferating and migrating cells push and stretch solid components of the surrounding tissue. They are large enough to compress blood and lymphatic vessels in and around tumors, impairing blood flow and the delivery of oxygen, drugs and immune cells,” Jain says.

Elevated interstitial fluid pressure is caused by abnormally permeable blood vessels in tumors leaking blood plasma into tissues surrounding the tumor, and by insufficient drainage of lymphatic fluid. The interstitial fluid carries various growth factors with it, causing edema (swelling), elution (release) of drugs and growth factors, and facilitating cancer invasion of local and distant tissues.

Increased stiffness is caused by the deposition of cellular matrix (scaffolding) and remodeling of tissues. This stiffness has traditionally been used as a diagnostic marker for tumor growth, and more recently it has come to be recognized as a marker for prognosis. Increased stiffness activates signaling pathways that promote proliferation, invasiveness and metastasis of cancer cells, Jain explains.

“Finally, when normal tissue architecture is disrupted by cancer growth and invasion, micro-architecture is altered,” he says. “Stromal (supporting) cells, cancer cells and extracellular matrix adopt new organization. This changes the interactions between an individual cell and its surrounding matrix and cells, which affects signaling pathways associated with invasion and metastasis.”

Li’l Kurt is a genetic marvel.

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In an effort to increase genetic diversity among horses, scientists have gone sci-fi and used frozen 40-year-old cells to create Kurt, the very first clone of a Przewalski’s horse.

🐴 You love badass animals. So do we. Let’s nerd out over them together.