Study finds two distinct patterns of metastatic spread in human colorectal cancer — ScienceDaily

A study led by Massachusetts General Hospital (MGH) investigators has found that the traditional model for the spread of carcinoma, the deadliest form of cancer — from the primary tumor, to nearby lymph nodes, to other organs — may not apply in all cases. In their report in the July 7 issue of Science, the researchers describe finding that, for the majority of colorectal cancer patients in the study, “distant” metastases originated directly from the primary tumor, independent of any lymph node metastases.

“Our results provide the first evidence in humans that the century-old ‘lymph node metastases are precursors of distant metastases’ model does not apply to all or even most colorectal cancers,” says lead and corresponding author Kamila Naxerova, PhD, of the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology. “These findings fill an important gap in our knowledge of metastatic disease evolution and have the potential to guide improvements in the clinical management of lymph node metastases.”

The current study is a follow-up to a 2014 report in which Naxerova and her colleagues described a simple assay that could reveal evolutionary relationships between tumors at various sites in a patient’s body. Based on analysis of small, mutation-prone segments of the genome called polyguanine (poly-G) repeats, that study found that relationships between primary and metastatic tumors were different in each case — for example, in some patients metastatic spread occurred early and in others late in tumor development. The assay was also able to identify specific areas within a primary tumor that had been the source of specific metastases, based on their genetic profiles.

Treatment for most solid tumors now incorporates what are called TNM — primary tumor (T), nodal metastasis (N), and distant metastasis (M) — staging schemes. Patients with lymph node metastases are known to have a higher likelihood of developing distant metastases, implying a link between the two. But in several recent clinical trials the removal of metastatic lymph nodes did not always improve patient survival, casting doubt on the relationship between nodal and distant metastasis. To better understand relationships between primary tumors and the two types of metastases, the researchers used poly-G typing to analyze more than 200 tissue samples of primary tumors, lymph node metastases and distant metastases from 17 patients with colorectal cancer.

In 35 percent of these patients, the results indicated that both lymph node and distant metastases had arisen from the same cell type in the primary tumor, findings compatible with the scenario of spread from the primary tumor to lymph nodes and then to distant sites. However, in 65 percent of patients, poly-G typing showed that lymph node and distant metastases cell types were different and matched different cell types within the primary tumor, indicating independent origins for these metastasis types.

Naxerova says, “We now suspect that lymph node metastases simply indicate the presence of an aggressive primary tumor, rather than being directly responsible for the formation of distant metastases. Now we need to investigate whether clinical outcomes for patients whose lymphatic and distant metastases have common origins are different from those of patients whose metastases have distinct evolutionary origins. If there is a difference, our assay might be a useful prognostic test in the future.” Naxerova is a Research Fellow at the Edwin L. Steele Laboratories and at the Division of Genetics at Brigham and Women’s Hospital and Harvard Medical School.

Rakesh K. Jain, PhD, director of the Steele Labs, Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School, and senior author of the Science paper, says, “Lymph nodes are usually considered as contributors to distant metastases. Yet multiple retrospective and prospective studies have shown that complete dissection of lymph nodes does not confer survival advantage in a number of malignancies. Our study provides the first direct genetic evidence towards resolving this enigma.”

Study co-author Jochen K. Lennerz, MD, PhD, of the Center for Integrated Diagnostics in the MGH Department of Pathology, adds, “Typing, grading, and staging — our traditional cancer assessment tools — cannot account for the relationships between cancer at multiple sites. Now, we have a new, effective way of looking at disseminated cancer. Given that this test is cost-effective, we are excited to bring it to the clinic as soon as possible.”

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Zoning in on specifics of Mediterranean diet for colorectal health — ScienceDaily

The benefits of a “Mediterranean diet” (MD) are well-known when it comes to colorectal protection, but it’s hard to know specifically what elements of the diet are the healthiest.

Now a new study, presented today at the ESMO 19th World Congress on Gastrointestinal Cancer suggests loading up on fish and fruit, and cutting back on soft drinks are the three most important things.

“We found that each one of these three choices was associated with a little more than 30% reduced odds of a person having an advanced, pre-cancerous colorectal lesion, compared to people who did not eat any of the MD components. Among people who made all three healthy choices the benefit was compounded to almost 86% reduced odds,” said Naomi Fliss Isakov, PhD fromTel-Aviv Medical Center, in Tel Aviv, Israel.

Colorectal cancer (CRC) develops from intestinal polyps and has been linked to a low-fibre diet heavy on red meat, alcohol and high-calorie foods, said Fliss Isakov.

And while the Mediterranean diet has been associated with lower rates of colorectal cancer, the definition of what elements in the diet are the most beneficial, has not always been clear.

Using dietary questionnaires from 808 people who were undergoing screening or diagnostic colonoscopies, the research team was able to dig down to look at the fine details of their daily meals.

All subjects were between 40 and 70 years old, without high risk of CRC, and answered a food frequency questionnaire.

Adherence to the MD components was defined as consumption levels above the group median for fruits, vegetables and legumes, nuts and seeds, whole grains, fish and poultry and a high ratio of monounsaturated to saturated fatty acids, as well consumption below the median of red meat, alcohol, and soft drinks.

The investigators found that compared to subjects with clear colonoscopies, those who had advanced polyps reported fewer components of the Mediterranean diet (a mean of 1.9 versus 4.5 components). Yet even consumption of two to three components of the diet, compared to none, was associated with half the odds of advanced polyps.

Odds were reduced in a dose response manner with additional MD components — meaning that the more MD components people adhered, the lower their odds of having advanced colorectal polyps.

After adjusting to account for other CRC risk factors, including other dietary components, the researchers narrowed in on high fish and fruit and low soft drinks as the best combo for reduced odds of advanced colorectal polyps.

The next step will be to see whether the MD is linked to lower risk of CRC in higher risk groups, she concluded.

Commenting on the study, ESMO spokesperson Dirk Arnold, MD, PhD, from Instituto CUF de Oncologia in Lisbon, Portugal, said “this large population-based cohort-control study impressively confirms the hypothesis of an association of colorectal polyps with diets and other life-style factors. This stands in line with other very recent findings on nutritive effects, such as the potential protective effects of nut consumption and Vitamin D supplementation which have been shown earlier this year. However, it remains to be seen whether these results are associated with reduced mortality, and it is also unclear if, and when a dietary change would be beneficial. Despite this lack of information, it makes sense to consider this diet for other health-related reasons also.”