In the Lab

On Cancer: New Findings Clarify How Kidney Cancer Spreads to Distant Organs

By Eva Kiesler, PhD, Science Writer/Editor  |  Wednesday, December 19, 2012
Pictured: X-ray Image This X-ray image shows metastatic bone tumors in a mouse with kidney cancer. The metastatic tumors appear as hollow or dark areas in the bones.

Metastasis, the process by which some tumors spread from their site of origin to other body parts, accounts for more than nine out of ten cancer-related deaths. But scientists still know relatively little about the genes and biological processes that cause metastasis to occur — information that potentially could translate into new ways to stop cancers from reaching advanced or terminal stages.

Now a Memorial Sloan Kettering research team has shed light on the mechanisms by which kidney cancer metastasizes to distant organs, including the lungs, bone, and brain. Published in the journal Nature Medicine in December, the findings point to potential therapeutic strategies to control the spread of the disease. The study also offers scientific insights that could advance metastasis research in other cancer types.

Focusing on Kidney Cancer

The research was led by cancer biologist Joan Massagué, Chair of the Sloan Kettering Institute’s Cancer Biology and Genetics Program and Director of the Metastasis Research Center. In recent years, his laboratory has uncovered basic causes of metastasis in a number of cancer types, including breast and lung cancers.

“In this study, we focused on clear cell renal cell carcinoma, the most common subtype of kidney cancer, for which there is an urgent need for more-effective therapies,” says postdoctoral fellow Sakari Vanharanta, the first author of the Nature Medicine report. “The metastatic form of this disease is almost always incurable.”

In the vast majority of patients, clear cell renal cell carcinoma (ccRCC) tumors carry DNA changes in a gene called VHL. These mutations have been shown to cause the formation of primary kidney tumors, but they do not necessarily lead to metastasis. Until recently, researchers did not know what makes some renal cell carcinoma cells capable of forming secondary tumors in distant organs.

New Potential Drug Targets

In the recent study, the team addressed this question by performing experiments in mouse models and cell lines, and by analyzing biological and clinical data from more than 700 patients with ccRCC, whose tumors had been analyzed in large-scale cancer genomics projects.

They discovered that two genes called CYTIP and CXCR4 are activated in metastatic tumor cells but inactive in non-metastatic cells. Their experiments suggest that the activation of the two genes might be essential for the spread of kidney cancer.

CXCR4 has been linked to metastasis before in this and other tumor types, including breast cancer,” Dr. Vanharanta says. “Now, our study shows that blocking CXCR4 function with a drug called plerixafor can reduce kidney cancer metastasis in mice.” Plerixafor (MozobilTM) is currently used to stimulate blood stem cells in some cancer patients treated by bone marrow transplantation.

The researchers plan to investigate further whether CXCR4 and CYTIP, and other genes identified in the study, might offer new targets for the development of more-effective drugs for kidney cancer.

Exploring the Epigenetics of Metastasis

In addition, the investigators explored the mechanisms by which the CXCR4 and CYTIP genes are switched on in kidney cancer cells to incite metastasis. Their study revealed that the genes undergo a series of epigenetic changes — modifications in the proteins that package a cell’s DNA and regulate genes.

Unlike gene mutations, which alter a cell’s genetic code, epigenetic changes leave the DNA sequence unaffected. Nevertheless, such changes can influence a cell’s behavior by switching individual genes on or off.

Epigenetic modifications are commonly seen in many types of cancer and have recently been associated with more-advanced disease. However, little is known about the specific genes and mechanisms by which tumor cells may reconfigure their epigenetic makeup, causing a person’s disease to progress and establish itself in new organs.

“Our study has demonstrated with clear examples how epigenetic alterations can lead to the activation of metastasis-inducing genes,” Dr. Vanharanta notes. “This is a conceptual advancement that is likely to help us understand how metastasis occurs in kidney cancer as well as in other cancer types.”

Comments

Congratulations!!!! to Director Joan Massague and PostDoc Sakari Vanharanta. This text was more understandable for me. Thank You!

Super research!! Congrats much!

This is what we patients truly need: new approaches, brave research, quick human tests! Thank you for your brilliant work! We live in hope.

Congratulations to Director Joan Massague and PostDoc Sakari Vanharanta!! I am a survivor of Renal Cell Carcinoma, which had matastised in my lung, aorta and liver through a clinical trial conducted by Dr. Motzer in 2004-2005 at MSKCC. It has been since then that I have been cured and survived through the clinical trial that gave me Pegalated Interferon. I am also a donor to MSKCC and am glad to see the research projects providing great results. Keep it up, you guys out there can do it and we can soon win the battles against cancer. God Bless!

Congrats to Drs on this valuable research. I am suffering from mRcc with lungs and bones having metastasis. I hope new medicine will come before I die. Sutent and Afinator have failed on me. Any valued advice for my survival will be appreciated. I have also shown to Dr James Heish of Sloan Memorial.

You have successfully blocked the gene CXCR4 in your laboratory mice to prevent metastasis. I have removed the kidney with ccRCC, stage III pT3a four and half years ago and no clear evidence of metastasis has been found as yet in 6 monthly follow up CT scans. I wish, my RCC is the same type as that of the mice and I would be glad to become a mice for a limited period of time !

I'm struggling with Stage 4 ccRCC that has metastasized to adrenal gland and lower spine (golf ball sized tumor on S1/S2-tail bone). The spinal metastasis has left me totally disabled, without bowel control, inability to urinate, and inability to walk more than about 10 feet. The study results shown here are spectacular. This research won't help repair nerve damage done to my spine, but hopefully I will last long enough on Sutent to receive any benefits from this research. Thank you Drs!

Keep up the good work. I have stage 4 RCC and my hope is that the available treatments can keep me going until this disease can be beaten properly. Your work is appreciated more than you will ever know. Thank you.

My 85 y/o father, in relatively good health, was just Dx with Kidney cancer with metastasis via CT Scan. I do not yet know to where. He is meeting with a Urologist this week and an oncologist next week. Is it 'wise' to perform surgery or chemotherapy in a man of this age? He is the primary caretaker of my 85 y/o mother with dementia, requiring 24/7 'supervision. Please advise. I'll soon know the extent of the metastasis. William

William, unfortunately we are unable to answer specific medical questions on our blog. If you would like to make an appointment with a Memorial Sloan-Kettering physician, please call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thanks for your comment.

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