Changes in fat metabolism increases the risk of prostate cancer metastasis

Nature Communications, researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC) shed new light on the genetic mechanisms that promote metastasis in the mouse model and also implicated the typical Western high-fat diet as a key environmental factor driving metastasis. Although it is widely postulated that a Western diet can promote prostate cancer progression, direct evidence supporting a strong association between dietary lipids and prostate cancer has not been considered.

Epidemiological data links dietary fats (and obesity) to many types of cancer, and rates of cancer deaths from metastatic cancers including prostate cancer. The progression of cancer to the metastatic stage represents a pivotal event that influences patient outcomes and the therapeutic options available to patients. Available data provide a strong genetic foundation for the mechanisms underlying metastatic progression, and also demonstrated how environmental factors can boost these mechanisms to promote progression from primary to advanced metastatic cancer.

The tumor suppressor gene PTEN is known to play a major role in prostate cancer; its partial loss occurs in up to 70 percent of primary prostate tumors. Its complete loss is linked to metastatic prostate disease, but animal studies suggest the loss of PTEN alone is not enough to trigger progression. Pandolfi and colleagues sought to identify an additional tumor suppressing gene or pathway that may work in concert with PTEN to drive metastasis.

Looking at recent genomic data, Pandolfi and colleagues noticed that another tumor suppressor gene, called PML, tended to be present in localized (non-metastatic) prostate tumors, but was absent in about a third of metastatic prostate tumors. Moreover, about 20 percent of metastatic prostate tumors lack both PML and PTEN. When they compared the two types of tumor - the localized ones lacking only the PTEN gene versus the metastatic tumors lacking both genes - the researchers found that the metastatic tumors produced huge amounts of lipids, or fats.

 In tumors that lacked both PTEN and PML tumor suppressing genes, the cells' fat-production machinery was running amok.  Discovered in 2009, a molecule named "fatostatin" is currently being investigated for the treatment of obesity. Pandolfi and colleagues tested the molecule in lab mice. The obesity drug blocked the lipogenesis fantastically and the tumors regressed and didn't metastasize.

In addition to opening the door to new treatment for metastatic prostate cancer, these findings also solve a long-standing scientific puzzle. For years, researchers had difficulty modeling metastatic prostate cancer in mice, making it hard to study the disease in the lab. Mice are fed with saturated fat, the type found in food cheeseburgers and fries - in the animals' diet, the mice developed aggressive, metastatic tumors.

The findings could result in more accurate and predictive mouse models for metastatic prostate cancer, which in turn could accelerate discovery of better therapies for the disease. Additionally, physicians could soon be able to screen their early-stage prostate cancer patients for those whose tumors lack both PTEN and PML tumor suppressing genes, putting them at increased risk for progressing to metastatic disease. These patients may be helped by starving these tumors of fat either with the fat-blocking drug or through diet.
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How cancer spreads

A University of Hawai'i Cancer Center researcher has identified how some cancer cells are made to move during metastasis. The research provides a better understanding of how cancer spreads and may create new opportunities for cancer drug development. Metastasis causes the deaths of 90 percent of cancer patients.

The spread of cancer by metastasis is driven by a set of mutant proteins called oncogenes which cause cancer cells to multiply uncontrollably and promotes their ability to move. How oncogene activity specifically directs the increased movement and metastasis is highly complex and remains largely unknown.

 RSK2 protein forms a signaling hub that includes proteins called LARG and RhoA. They show that turning on this signaling hub activates the movement of the cancer cells. These results significantly advance understanding of how cancer cells are made to move during metastasis and may provide more precise targets for drugs to stop cancer metastasis in patients where there are oncogenic mutations.
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Links between cholesterol and breast cancer

High cholesterol levels have been associated with breast cancer spreading to other parts of the body, researchers discovered that the byproduct of cholesterol metabolism that acts on specific immune cells so that they facilitate the cancer's spread instead of stopping it is responsible for the spread.

Many women will experience metastatic breast cancer, when the breast cancer has spread to other organs, and at that point, there is no effective therapies.

Researchers fed mice with breast cancer tumors a diet high in cholesterol. They confirmed that high levels of cholesterol increased tumor growth and metastasis, and that mice treated with statins cholesterol lowering drugs had less metastasis.

Human body's immune system has the capacity to attack cancer but the cholesterol metabolite hydroxycholestrol 27HC works on immune cells and prevents them from attacking cancer because 27HC acts through the immune system, and not on the breast cancer.
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Causes and prevention of colon cancer

Colon cancer occurs in the large intestine or in the rectum, it develops slowly. An abnormal growth known as a polyp develops on the inner lining of the large intestine or rectum before the cancer growth.

Familial adenomatous polyposis, a devastating inherited disease that causes pre-cancerous polyps to grow in the intestine at a young age, often leading to the removal of portions of the colon to prevent cancer.

 CtBP drives the actions of what are known ascancer stem cells, which are keys to cancer metastasis and resistance to chemotherapy. CtBP is not mutated in colon cancer; instead, it is overexpressed to the point where the cancer depends on it for growth.

CtBP works to reprogram cells by repressing the expression of genes that typically prevent cancer through a form of cell suicide known as apoptosis while simultaneously promoting the expression of other genes that lead to cancer growth and metastasis.

The researchers found that CtBP can cause normal human cells to become cancerous when inserted into the cell's DNA. In mouse models of familial adenomatous, treatment with HIPP significantly reduced intestinal polyps and increased survival while mice bred without the CtBP gene lived twice as long as those with it.

HIPP acted as a chemical to prevent polyp formation, thereby reducing the risk of colon cancer. Anti-CtBP therapies such as HIPP may be able to complement current therapies to counter drug resistance and decrease metastasis to control and cure colon cancer.
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Grape seed may prevent colon cancer

The combination of resveratrol and grape seed extract is very effective in preventing and treating colon cancer.

Cancer stem cells are capable of self-renewal, cellular differentiation and maintain their stem cell-like characteristics even after invasion and metastasis.

When taken separately in low doses, resveratrol and grape seed extract are not effective against cancer stem-cell, but effective in suppressing cancer when they were combined.

The combination of grape seed and resveratrol can prevent the recurrence of colon cancer in survivors.
When tested on mice, it suppressed tumours in mice fed with the compound.

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