Experiencing cancer, whether directly or indirectly, is never a pleasant ordeal. At some point a question might invariably be asked: just what is it that makes cancer so difficult to rid of? The treatment of patients with anticancer drugs, chemotherapy, is notorious for inducing side effects, since the medication could also target and eliminate surrounding normal cells. Yet unfortunately despite such intensive and often costly procedures, the disease could persist and stage a stronger comeback.
One explanation is that the high rate of genetic mutations in cancer cells enables them to develop resistance to the drug. Another explanation is that the drugs were not able to completely eliminate all cancer cells. But how about the idea that anticancer drugs itself promotes the resistance and survival of cancer cells?
This was a finding reported by Anna Obenauf and Joan Massague last year. It is a surprising and frankly unwelcoming revelation, but before going into details on the study, it is worthwhile to take a detour on one of the hottest rages in cancer research nowadays.
Scientists have come leaps and bounds in understanding cancer. Certain concepts have been entrenched in public perception, none more so than the impression of cancer cells as out-of-control mutants, capable of perpetual cell division. The dividing mass of cells develops into a tumour. As the tumour grows larger, cancer cells within it needs to take more oxygen and nutrients for survival. Cancer cells can shed from the original site into the bloodstream, and thereby infiltrate other body organs and establish new tumours. Indeed, the spread of cancer (scientifically termed as “metastasis”) is highly damaging to the patient’s body and is a main cause of fatality.
It is thus easy to see tumours as rogues acting on their own, aggressively and selfishly hoarding resources from surrounding healthy cells. Indeed, many anticancer drugs have been developed to stop cancer by means of targeting, blocking or correcting unique characteristics that are manifest in cancer cells.
This picture, however, is becoming increasingly outdated. For a start, it turns out that tumours are actually heterogenous: instead of a monotonous body expected after endless cell replications, sub-groups of cancer cells that differ in genetic character could be identified. Secondly, this variety is dependent on the tumour’s context, known as the tumour microenvironment (TME).
The TME is essentially a neighbourhood. Its residents are the non-cancerous cells, which work together to sustain a community – that higher level of cellular organisation known as the tissue. Such residents include the immune cells, which mount protective responses against foreign infection or damages; the vascular network containing blood vessels and supporting cells, for bringing nutrients; and the stroma cells, which maintain the structural integrity of the whole tissue by releasing chemicals.
A rogue, regardless of how wickedly ingenious he is (even fictional constructs like the Joker), still relies on the infrastructure and characters in a society to achieve whatever deeds he has in mind. In the world of cancer, the same is true. In the past decade, it has been increasingly apparent that cells in the TME are actively involved in supporting nearly all aspects of tumour activity. Glioblastomas, one of the most aggressive forms of brain cancer, are marked by specific presence of pericytes, which is a type of vascular supporting cell that wraps around blood vessels. This has the effect of strengthening the vessel network, which in turn provides more nutrients and contribute to an aggressive tumour growth. In another example, a type of stroma cell called cancer-associated fibroblast is present in high abundance in tumour tissues. They play diverse set of roles: from re-shaping the tissue structure to allow easier metastasis of cancer cells, or in stimulating normal cells to turn cancerous. In 2009, researchers led by Seiji Yano of Kanazawa University also discovered that such cells were attracted and accumulate closely to lung cancer cells. Importantly, these accumulating cancer-associated fibroblasts also released a substance known as HGF that made the cancer cells drug-resistant.
These are only two cell types out of many, and chances are that more remains to be discovered. And that is not to exclude the interactions between TME and cancer cells (as in the case of the Yano study) and within TME cells. Finally, just as tumours are heterogenous, scientists are also faced to tackling the challenge of TME heterogeneity, each neighbourhood dynamic and shifting in its cellular composition, in order to provide the best environment to nurture cancer growth and movement.
The complexity of TMEs is truly mind-boggling, and its influence on future cancer treatment is only beginning to be explored. At this point, the findings from Obenauf and Massague are a revealing example.
Certain types of skin cancer and lung cancer have been known to show resistance to a particular class of drug in chemotherapy, called the kinase inhibitors (KI). Although initial treatment could stabilise the disease, resistance comes invariably six to 12 months after, and this has been suggested because of the presence of a small population of KI-resisting cells. By causing tumours to regress, chemotherapy invariably changes the TME environment, and Obenauf and Massague wanted to find how such resistant cells respond to such changes.
To study this, they first injected cancer cells in mice to generate skin tumours, and then treated the mice with or without vemurafenib (a KI drug). As expected, in tumours that are generated solely from KI-sensitive cancer cells, the drug treatment caused their regression. In tumours that are generated from a heterogenous mixture of KI-resistant and KI-sensitive cancer cells, vemurafenib also decreased their volume, but researchers discovered that such regressed tumours contained a high number of drug-resistant cells that proliferates strongly. Interestingly, this observation was absent in tumours generated only from drug-resistant cancer cells. Thus, it seems that the growth advantage incurred by resistant cells was not due to the direct effects of vemurafenib on KI-resistant or KI-sensitive cells, but linked to the regressing population of KI-sensitive cells upon treatment.
What is more, in another set of experiments, the scientists also showed that the KI-treated regressing tumour could attract resistant cancer cells that circulate in the bloodstream during metastasis. Clearly, beyond its therapeutic function, vemurafenib treatment unwittingly stimulates an unintended consequence that reinforces the growth of resistant cells.
So what exactly is responsible for all of this?
As KI-sensitive cells are effectively targeted by the drug, the scientists hypothesized that certain signals released after treatment (and its associated regression of the TME) could re-establish the growth of the minority, KI-resistant cell clones present in tumours. They found out the resistant cells showed higher proliferation or migration rate, after being cultured in ‘recycled’ growth media previously used by cancer cells that underwent vemurafenib treatment. This led the researchers to suggest of a “therapy-induced secretome” response. To identify what might be the possible molecular components and genes needed to activate this ‘secretion’, the team analysed gene expression data in the sensitive cancer cells after drug treatment, and identified 473 genes which showed altered expression, as well as one of the mediating proteins. The scientists also pinpointed the involvement of several cellular signalling pathways. Interestingly, one of them, PI(3)K/AKT, could be activated by a protein that happens to be abundantly expressed in the tumour microenvironment.
It has to be stressed again, that the findings were based on the actions of specific anticancer drugs (KIs) and on skin and lung cancer samples. Nonetheless, it does offer an appreciation on the impact of the TME. Is this extra level of influence a hindrance to current cancer treatment? Whilst the discovery of a therapy-induced secretome appears discouraging, on the bright side it presents new avenues to tackle the problem of drug resistance. Towards the end of the same study, by using a combinational treatment of vemurafenib and inhibitors of the PI(3)K/AKT pathway, the tumour growth could be effectively blunted. Indeed, a similar approach was also demonstrated in the aforementioned Yano study.
And this is only the therapeutic aspect. As Tadashi Tsujino showed in a 2007 paper, analysis of gene expression profiles from TME cells (in this case, a type called myofibroblasts) was an effective predictor of colorectal cancer recurrence in patients that have undergone surgery before, thus also highlighting a potential of using TME as diagnostic tools in the clinic.
So, much exciting times ahead indeed for cancer researchers.
Obenauf, Anna C., et al. “Therapy-induced tumour secretomes promote resistance and tumour progression.” Nature 520 (2015): 368-72.
Tadashi, Tsujino, et al. “Stromal Myofibroblasts Predict Disease Recurrence for Colorectal Cancer” Clinical Cancer Research 13.7 (2007): 2082-90.
Wei, Wang, et al. “Crosstalk to Stromal Fibroblasts Induces Resistance of Lung Cancer to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.” Clinical Cancer Research 15.21 (2009): 6630-38.
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