Prostate Cancer Spreads to Bones by Overtaking the Home of Blood Stem Cells

ScienceDaily (Mar. 24, 2011) — Like bad neighbors who decide to go wreck another community, prostate and breast cancer usually recur in the bone, according to a new University of Michigan study.

This is a drawing of prostate cancer cells in the bone marrow niche.

Now, U-M researchers believe they know why. Prostate cancer cells specifically target and eventually overrun the bone marrow niche, a specialized area for hematopoietic stem cells, which make red and white blood cells, said Russell Taichman, professor at the U-M School of Dentistry and senior author of the study.

Once in the niche, the cancer cells stay dormant and when they become active again years later, that's when tumors recur in the bone. The implication is that this may give us a window as to how dormancy and recurrence take place.

Taichman and a team of researchers looked in the bone marrow and found cancer cells and hematopoietic stem cells next to one another competing for the same place. The finding is important because it demonstrates that the bone marrow niche plays a central role in bone metastasis -- cancers that spread into the bone -- giving researchers a new potential drug target.

Drugs could be developed to keep the types of cancers that likely recur in the bone from returning, Taichman said. For example, these drugs could either halt or disrupt how the cancer cells enter or behave in the niche, or keep the cancer cells from out-competing the stem cells.

Cancer cells act a lot like stem cells in that they must reproduce, so the U-M research group hypothesized that prostate cancer cells might travel to the niche during metastasis. One of the jobs of the niche is to keep hematopoietic stem cells from proliferating -- which may be the case for cancer cells, as well, the researchers found.

So why does cancer recur? Say a person has a tumor and surgeons cut it out or do radiation, but it recurs in the bone marrow five years later, Taichman said. Those cancer cells had been circulating in the body well before the tumor was discovered, and one place those cancer cells hid is the niche.

"So what have the cancer cells been doing during those five years? Now we have a partial answer -- they've been sitting in this place whose job it is to keep things from proliferating and growing," Taichman said.

"Our work also provides an explanation as to why current chemotherapies often fail in that once cancer cells enter the niche, most likely they stop proliferating," said Yusuke Shiozawa, lead author of the study. "The problem is that most of the drugs we use to try to treat cancer only work on cells that are proliferating."

Metastases are the most common malignant tumors involving the skeleton, and nearly 70 percent of patients with breast and prostate cancer have bone involvements. Roughly 15 percent to 30 percent of patients with lung, colon, stomach, bladder, uterus, rectum, thyroid or kidney cancer have bone lesions.

Researchers aren't quite sure how the cancer cells out-compete the stem cells in the niche. However, they do know the stem cells were displaced because when cancer cells were in the niche scientists also found evidence of immature blood stem cells in the blood stream, instead of in the marrow where they were supposed to be, Taichman said.

"Eventually the entire blood system is going to collapse," he said. "For example, the patient ultimately becomes anemic, gets infections, and has bleeding problems. We really don't know why people with prostate cancer die. They end up dying from different kinds of complications in part because the marrow is taken over by cancer."

The next step is to find out how the tumor cell gets into the niche and becomes dormant, and exactly what they do to the stem cells when they are there. Researchers also want to know if other types of cancer cells, such as breast cancer, also go to the niche.

The study appears online in the Journal of Clinical Investigation.

Co-authors are: Elizabeth Pedersen, Aaron Havens, Younghun Jung, Anjali Mishra, Jeena Joseph, Jin Koo Kim, Anne Ziegler, Michael Pienta, Jingcheng Wang, Junhui Song and Paul Krebsbach of the U-M School of Dentistry; Lalit Patel, Chi Ying, Robert Loberg and Kenneth Pienta of the departments of Urology and Internal Medicine at the U-M Medical School.

Key Protein Suppresses Prostate Cancer Growth in the Laboratory

ScienceDaily (Mar. 22, 2011) — Cancer researchers have discovered an important protein, produced naturally inside cells, that appears to suppress the growth of prostate cancer cells in the laboratory. The findings, published February 1 in the journal Cancer Research, offer promising leads for research towards new treatments.

Prostate cancer is the most common cancer among men in the UK, with 37,500 men diagnosed with the disease every year. Many prostate cancers are slow growing, but in some cases the cancer is aggressive and spreads to other parts of the body, such as the bone. These cases are much more likely to be fatal.

In the new study, scientists at Imperial College London found that a protein called FUS inhibits the growth of prostate cancer cells in the laboratory, and activates pathways that lead to cell suicide.

The researchers also looked for the FUS protein in samples from prostate cancer patients. They found that in patients with high levels of FUS, the cancer was less aggressive and was less likely to spread to the bone. Higher levels of FUS also correlated with longer survival. The results suggest that FUS might be a useful marker that can give doctors an indication of how aggressive a tumour will be.

"At the moment, there's no way to say whether a prostate tumour will kill you or be fairly harmless," said Dr Charlotte Bevan, senior author of the study, from the Department of Surgery and Cancer at Imperial College London. "Current hormonal therapies only work for a limited time, and chemotherapy is often ineffective against prostate cancer, so there's a real need for new treatments.

"These findings suggest that FUS might be able to suppress tumour growth and stop it from spreading to other parts of the body where it can be deadly. It's early stages yet but if further studies confirm these findings, then FUS might be a promising target for future therapies."

Prostate cancer depends on male hormones to progress as these hormones stimulate the cancer cells to divide, enabling the tumour to grow. Treatments that reduce hormone levels or stop them from working are initially effective, but eventually the tumour stops responding to this treatment and becomes more aggressive.

Dr Bevan and her team began by exposing prostate cancer cells to male hormones and looking at how the levels of different proteins changed. They discovered that the hormones made the cells produce less of the FUS protein, and examined further whether FUS might influence cell growth by inserting extra copies of the gene for FUS into cells grown in culture. They found that making the cells produce more FUS led to a reduction in the number of cancer cells in the dish.

Greg Brooke, first author of the study, from the Department of Surgery and Cancer at Imperial College London said: "Our study suggests that FUS is a crucial link that connects male hormones with cell division. The next step is to investigate whether FUS could be a useful test of how aggressive prostate cancer is. Then we might look for ways to boost FUS levels in patients to see if that would slow tumour growth or improve response to hormone therapy.

"If FUS really is a tumour suppressor, it might also be involved in other cancers, such as breast cancer, which has significant similarities with prostate cancer."

The study was funded by Prostate Action, the Medical Research Council, the Imperial College Experimental Cancer Medicine Centre (set up with a grant from Cancer Research UK and the Department of Health) and the Prostate Cancer.

Novos exames detectam o câncer de próstata

Uma descoberta de cientistas islandeses promete tornar mais preciso e menos invasivo o diagnóstico de câncer de próstata. Eles desenvolveram um novo teste de PSA (sigla de antígeno prostático específico e marcador para a doença) personalizado, através da observação de certas variações genéticas.

O PSA ainda é visto com desconfiança, até mesmo por parte de alguns médicos, porque é difícil definir quais são os seus níveis normais; às vezes o câncer não é detectado ou ocorrem falsos positivos. E o PSA ainda pode aumentar por razões não relacionadas ao câncer. Por outro lado, homens com um PSA abaixo de 2,5 nanogramas por mililitro podem ter a doença e não saber.

Então os cientistas pensaram em personalizar esse exame, a partir da análise de perfis genéticos individuais; e esse pode ser um passo para evitar biópsias desnecessárias em pacientes de baixo risco. No estudo, publicado na revista Science Translational Medicine, os islandeses da companhia Decode Genetics descobriram varias mutações do DNA, conhecidas como SNP, que afetam os níveis sanguíneos de PSA. William Catalona, professor de urologia na Universidade Northwestern, em Illinois - que ajudou a desenvolver o teste de PSA original e participou da investigação atual - diz que agora ficou claro porque que alguns homens têm naturalmente níveis altos ou baixos PSA.

O câncer de próstata é o mais comum nos homens ocidentais e mata 250 mil anualmente, mas pode ser curado se detectado no início. No futuro, dizem especialistas, analisar as variações genéticas que afetam os níveis de PSA poderia permitir criar ferramentas muito mais precisas em termos individuais.

Segundo o uro-oncologista Luiz Carlos Miranda, da Sociedade Brasileira de Urologia-RJ, o exame de PSA personalizado ainda é um protocolo de pesquisa, e diz que há outro novo teste já usado em alguns países que melhora o diagnóstico do tumor maligno: o PCA3, feito através da coleta da urina. Ele deve ser associado ao atual exame de PSA, de rotina, ao toque retal.

Segundo urologistas, a investigação do gene PCA3 potencializa as chances de identificação de células do câncer de próstata em pacientes com PSA alto. Esse método de diagnóstico já está em uso no Chile e se acredita que até o segundo semestre de 2011 estará disponível para os brasileiros. O exame também está em uso em Alemanha, Holanda e Inglaterra. Mas o seu preço ainda é alto. Em Portugal, por exemplo, custa 300 euros.

Estudo descobre como eliminar proteína que reproduz câncer de próstata

Testes ainda só foram feitos em ratos, 

mas geram esperança de maior efetividade no tratamento

Um estudo da Universidade da Califórnia em Los Angeles (UCLA) revela a função de uma proteína na reprodução do câncer de próstata, e sua inibição em testes de laboratório gera esperança de uma maior efetividade no tratamento da doença.

"Descobrimos que, no mecanismo de autorrenovação das células-tronco, há uma proteína chamada Bmi-1, que também faz com que as células cancerígenas se reproduzam, particularmente no câncer de próstata", disse a médica Rita Lukacs, da UCLA.

"Em testes com células de próstata de ratos, descobrimos que, ao inibir a proteína Bmi-1, no caso de um câncer médio, podemos eliminá-lo completamente, e em mutações mais agressivas reduzimos a velocidade do desenvolvimento da doença", explicou a médica.

Rita é a principal pesquisadora do método alternativo para tratamento do câncer de próstata do Centro Eli and Edythe Broad para pesquisa de células-tronco e medicina regenerativa da UCLA.

Ao longo de três anos, a pesquisadora trabalhou para buscar uma maneira de evitar o crescimento do câncer de próstata nos laboratórios da universidade. Os resultados das pesquisas, efetuadas em células cancerígenas de animais, foram publicados na última quinta-feira, na edição antecipada na internet da revista médica Cell Stem Cell.

"Essa descoberta é uma esperança para os doentes de câncer de próstata. No entanto, os testes só foram feitos em ratos e faltam muitos procedimentos para começarmos testes em humanos", destacou Rita.