Targeting the Tumor Microenvironment May Aid in Treatment of Ovarian Cancer

Certain malignancies may possess a common and targetable matrix response, which affects disease pathogeneis, according to a recent study in Cancer Discovery. Findings of the paper were presented at the 12th Biennial Ovarian Cancer Research Symposium, held September 13–15 in Seattle.

“We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample,” wrote the study authors, led by Oliver M.T. Pearce, PhD, of Barts Cancer Institute, Queen Mary University of London, in Charterhouse Square, London.

The tumor microenvironment consists of a dynamic network of soluble factors, cytokines, chemokines, growth factors, and adhesion molecules. It is also responsible for extracellular matrix remodeling, proliferation of abnormal vascular and lymphatic networks, and cellular migration to and from the tumor mass. Abnormal deposition of the extracellular matrix, as well as aberrant organization, stiffens tumors and mediates cell and tissue mechanics.

From a historical perspective, cancer has been researched mostly on a genomic level focusing on the cancer cell. Little is understood about the tumor matrix environment, despite its importance during the initiation and spread of cancer.

In the current study, the team employed omental biopsies from high-grade serous ovarian cancer metastases, the most common and aggressive subtype of ovarian cancer. Using both early and late stage omental biopsies, they demonstrated the way in which nonmalignant cell densities and cytokine networks evolve with disease course.

The investigators defined gene and protein profiles that predicted the degree of disease and tissue stiffness using multivariate integration of different components of the extracellular matrix. They also uncovered the dynamic and complex nature of matrisome remodeling during the progression of metastases.

On the basis of a single metastatic site from one human malignancy, the investigators discovered a novel extracellular-matrix-associated molecular signature, or pattern of expression of 22 matrisome genes, which they coined the “matrix index.”

The matrix index predicted the extent of disease and tissue stiffness in the team’s sample set. This metric also differentiated patients with shorter overall survival in ovarian cancer as well as in 12 other types of cancer. This differentiation held regardless of patient age, stage, or response to primary treatment, thus indicating a common matrix response to both primary and metastatic cancers.

“The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease,” the authors concluded.

“Given that decades of targeting the epithelial tumor compartment have failed in substantially improving overall survival in patients with this deadly disease, there clearly is a need for a paradigm shift and new therapeutic targets. It is time to attack the tumor-supporting cells. One of the TME [tumor microenvironment] proteins described in this paper may be the long sought-after target that holds the key to clinical success,” wrote Ernst Lengyel, MD, PhD, professor and chair of obstetrics and gynecology at the University of Chicago Medical School, in response to the Pearce et al study published in Trends in Cancer.

Lengyel added that “the paper is a breakthrough in that it systematically studied what was a long ignored part of the tumor organ. Only by understanding both the cancer cells and the supporting tumor cells will we be able to understand and successfully target this deadly disease.”